The document discusses T cell development and selection in the thymus. Immature T cells enter the thymus with a random T cell receptor (TCR) repertoire that includes receptors harmful to the body. The thymus subjects these cells to positive and negative selection to purge harmful self-reactive cells and retain those useful for foreign antigen recognition in a process that establishes T cell tolerance. Positively selected cells have TCRs that recognize self-MHC molecules, making their recognition MHC-restricted and useful for the immune response.
Immune tolerance is induced through central and peripheral mechanisms that eliminate or suppress self-reactive immune cells. Central tolerance occurs in the thymus and bone marrow where high-affinity self-reactive T and B cells undergo apoptosis or receptor editing. Peripheral tolerance includes anergy induction, suppression by regulatory T cells (Tregs), and inhibition by receptors like CTLA-4 and PD-1. Tregs expressing the transcription factor FoxP3 are critical for maintaining tolerance and preventing autoimmunity. Failure of these tolerance mechanisms can lead to autoimmune disease.
Major Histocompatibility Complex
MHC:
• Major Histocompatibility Complex
– Cluster of genes found in all mammals
– Its products play role in discriminating self/non-self
– Participant in both humoral and cell-mediated immunity
• MHC Act As Antigen Presenting Structures
• In Human MHC Is Found On Chromosome 6
– Referred to as HLA complex
• In Mice MHC Is Found On Chromosome 17
– Referred to as H-2 complex
• Genes Of MHC Organized In 3 Classes
– Class I MHC genes
• Glycoproteins expressed on all nucleated cells
• Major function to present processed Ags to TC
– Class II MHC genes
• Glycoproteins expressed on macrophages, B-cells, DCs
• Major function to present processed Ags to TH
– Class III MHC genes
• Products that include secreted proteins that have immune functions. Ex. Complement system, inflammatory molecules
T cells are activated through the recognition of antigen peptides presented on MHC complexes on antigen presenting cells (APCs). This leads to T cell proliferation and differentiation into effector T cells. Cytotoxic T cells recognize endogenous antigens on MHC I to kill infected cells, while helper T cells recognize exogenous peptides on MHC II and secrete cytokines to stimulate macrophage activation or B cell antibody production. Full T cell activation requires both antigen recognition by the TCR and co-stimulatory signaling between molecules such as B7 and CD28.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
The document summarizes the complement system, including its three activation pathways (classical, alternative, and lectin), membrane attack complex, receptors, regulation, associated disorders, and laboratory assessment. It describes how the classical pathway is activated by antigen-antibody complexes, the alternative pathway does not require antibodies, and the lectin pathway is triggered by microbial polysaccharides binding to lectins or ficolins. Regulation is needed to prevent improper activation. Deficiencies can lead to increased infection risk or autoimmune diseases like SLE. Laboratory tests include measuring complement component levels.
The complement system is a group of proteins in the blood that helps antibodies and phagocytic cells destroy pathogens. It is activated via three pathways - classical, lectin, and alternative. Activation leads to a cascade of reactions that results in the formation of the membrane attack complex, which punches holes in the pathogen's cell membrane, killing it. Complement also aids in inflammation, phagocytosis, and immune adherence. The system is tightly regulated to prevent damage to host cells. Deficiencies can cause diseases like hereditary angioedema.
B cell generation-activation_and_differentiationDUSHYANT KUMAR
B cells develop through several stages:
1) Generation in the bone marrow or fetal liver
2) Activation in the lymph nodes through interaction with antigens and T cells
3) Differentiation into plasma cells, which secrete antibodies, or memory B cells
The key events in B cell activation and differentiation are Ig gene rearrangement, affinity maturation through somatic hypermutation, class switch recombination, and formation of plasma cells and memory cells mediated by AID and specific cytokines in germinal centers. B cells can be activated through T cell dependent or independent pathways.
This document provides information on MHC class I and class II molecules, including their structure, function, and role in antigen presentation. It discusses that MHC class I molecules are expressed on all nucleated cells and present intracellular antigens to CD8+ T cells. MHC class II molecules are expressed primarily on antigen presenting cells and present extracellular antigens to CD4+ T cells. The peptide binding grooves of MHC class I and II molecules differ in their structure and the size of peptides they can bind.
Immune tolerance is induced through central and peripheral mechanisms that eliminate or suppress self-reactive immune cells. Central tolerance occurs in the thymus and bone marrow where high-affinity self-reactive T and B cells undergo apoptosis or receptor editing. Peripheral tolerance includes anergy induction, suppression by regulatory T cells (Tregs), and inhibition by receptors like CTLA-4 and PD-1. Tregs expressing the transcription factor FoxP3 are critical for maintaining tolerance and preventing autoimmunity. Failure of these tolerance mechanisms can lead to autoimmune disease.
Major Histocompatibility Complex
MHC:
• Major Histocompatibility Complex
– Cluster of genes found in all mammals
– Its products play role in discriminating self/non-self
– Participant in both humoral and cell-mediated immunity
• MHC Act As Antigen Presenting Structures
• In Human MHC Is Found On Chromosome 6
– Referred to as HLA complex
• In Mice MHC Is Found On Chromosome 17
– Referred to as H-2 complex
• Genes Of MHC Organized In 3 Classes
– Class I MHC genes
• Glycoproteins expressed on all nucleated cells
• Major function to present processed Ags to TC
– Class II MHC genes
• Glycoproteins expressed on macrophages, B-cells, DCs
• Major function to present processed Ags to TH
– Class III MHC genes
• Products that include secreted proteins that have immune functions. Ex. Complement system, inflammatory molecules
T cells are activated through the recognition of antigen peptides presented on MHC complexes on antigen presenting cells (APCs). This leads to T cell proliferation and differentiation into effector T cells. Cytotoxic T cells recognize endogenous antigens on MHC I to kill infected cells, while helper T cells recognize exogenous peptides on MHC II and secrete cytokines to stimulate macrophage activation or B cell antibody production. Full T cell activation requires both antigen recognition by the TCR and co-stimulatory signaling between molecules such as B7 and CD28.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
The document summarizes the complement system, including its three activation pathways (classical, alternative, and lectin), membrane attack complex, receptors, regulation, associated disorders, and laboratory assessment. It describes how the classical pathway is activated by antigen-antibody complexes, the alternative pathway does not require antibodies, and the lectin pathway is triggered by microbial polysaccharides binding to lectins or ficolins. Regulation is needed to prevent improper activation. Deficiencies can lead to increased infection risk or autoimmune diseases like SLE. Laboratory tests include measuring complement component levels.
The complement system is a group of proteins in the blood that helps antibodies and phagocytic cells destroy pathogens. It is activated via three pathways - classical, lectin, and alternative. Activation leads to a cascade of reactions that results in the formation of the membrane attack complex, which punches holes in the pathogen's cell membrane, killing it. Complement also aids in inflammation, phagocytosis, and immune adherence. The system is tightly regulated to prevent damage to host cells. Deficiencies can cause diseases like hereditary angioedema.
B cell generation-activation_and_differentiationDUSHYANT KUMAR
B cells develop through several stages:
1) Generation in the bone marrow or fetal liver
2) Activation in the lymph nodes through interaction with antigens and T cells
3) Differentiation into plasma cells, which secrete antibodies, or memory B cells
The key events in B cell activation and differentiation are Ig gene rearrangement, affinity maturation through somatic hypermutation, class switch recombination, and formation of plasma cells and memory cells mediated by AID and specific cytokines in germinal centers. B cells can be activated through T cell dependent or independent pathways.
This document provides information on MHC class I and class II molecules, including their structure, function, and role in antigen presentation. It discusses that MHC class I molecules are expressed on all nucleated cells and present intracellular antigens to CD8+ T cells. MHC class II molecules are expressed primarily on antigen presenting cells and present extracellular antigens to CD4+ T cells. The peptide binding grooves of MHC class I and II molecules differ in their structure and the size of peptides they can bind.
B-cell maturation begins with hematopoietic stem cells in the bone marrow, where they develop through pro-B cell, pre-B cell, and immature B cell stages. During this process, immunoglobulin genes undergo rearrangement and expression of B cell receptors occurs. Immature B cells then migrate to secondary lymphoid tissues to complete maturation. Mature B cells circulate and are activated by antigen to proliferate and differentiate into plasma cells or memory B cells through T cell dependent or independent pathways. T cell dependent activation induces affinity maturation, class switching, and generation of long-lived memory B cells.
This document defines key terms related to antigens and the immune response. It discusses how antigens stimulate an immune response by interacting with antibodies and T cells. There are different types of antigens including exogenous antigens that enter the body from outside, endogenous antigens generated inside cells, autoantigens that are recognized by the immune system in autoimmune diseases, and tumor antigens expressed by cancer cells. The document also describes properties of antigens like immunogenicity and antigenicity, and characteristics of antigenic epitopes recognized by B cells and T cells. It classifies antigens as thymus-dependent or -independent and discusses conventional antigens, superantigens, and adjuvants that enhance immune responses.
Dr. Prem Mohan Jha presented on complement physiology. The complement system is part of the innate immune system and helps antibodies clear pathogens. It involves a biochemical cascade that is activated via three pathways: classical, lectin, and alternative. Complement activation leads to the formation of the membrane attack complex (MAC) which lyses cells. The complement system is tightly regulated to prevent damage to host cells. Deficiencies in complement components or regulators result in increased susceptibility to infections.
The document summarizes key aspects of T cell antigen receptor (TcR) structure and generation of diversity. It describes how TcR were discovered using monoclonal antibodies that recognize unique structures on T cell clones. TcR are heterodimers composed of α and β chains that are similar to antibody structures but do not undergo somatic hypermutation. TcR diversity is generated through combinatorial rearrangement of variable (V), diversity (D), and joining (J) gene segments, as well as junctional diversity from imprecise joining and addition of untemplated nucleotides.
B and T cell maturation involves three phases: 1) generation of antigen receptors through gene rearrangement, 2) refinement of antigen receptor repertoire through positive and negative selection, and 3) stimulation by foreign antigens. Positive selection ensures T cells recognize self MHC weakly, while negative selection eliminates those binding strongly to self antigens. The thymus tests T cells through these selection processes, with 98% of thymocytes undergoing apoptosis. Both B and T cells develop in specialized microenvironments, undergo gene rearrangement to generate diverse antigen receptors, and involve cell death via apoptosis.
The complement system consists of three pathways - the classical, lectin, and alternative pathways. The lectin pathway is activated when mannose-binding lectin (MBL) binds to mannose sugars on microbial surfaces. This binding activates MASP-1 and MASP-2, analogous to C1r and C1s in the classical pathway. MASP-1 and MASP-2 then cleave C4 and C2 to form the C3 convertase, which activates the remainder of the complement cascade. The lectin pathway thus provides an antibody-independent mechanism for complement activation in response to microbial pathogens.
The document discusses the major histocompatibility complex (MHC) in mammals. It notes that MHC acts as antigen presenting receptors and are involved in cell-cell interaction, antigen presentation, and recognition of self and non-self molecules. MHC is found on chromosome 6 in humans and is referred to as the HLA complex. MHC molecules are divided into three main classes - Class I MHC present antigens to cytotoxic T cells, Class II MHC present antigens to helper T cells, and Class III MHC genes encode complement components and cytokines. The structures and functions of Class I and Class II MHC molecules are described in detail.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
This document provides a summary of key cell surface markers (CD markers) for different immune cell types in humans and mice. It lists the main CD markers used to identify T cells, B cells, dendritic cells, NK cells, stem/precursor cells, macrophages/monocytes, granulocytes, platelets, erythrocytes, endothelial cells and epithelial cells in both species. It also provides some information on the functions of the Human Leukocyte Differentiation Antigens (HLDA) workshop which aims to standardize CD marker nomenclature.
The immunological synapse is the contact point between a T cell and antigen presenting cell where signaling and protein segregation occurs. It is composed of concentric rings called the central, peripheral, and distal supramolecular activation complexes. Signaling occurs through redistribution and segregation of receptors and proteins at the cell surface through both passive binding and active lateral movement and vesicle transport. Immunological synapses play a role in processes like HIV persistence through virological synapse formation between infected and uninfected T cells.
Cytokines are low molecular weight proteins or peptides that are important signaling molecules that regulate immunity and inflammation. They act as intercellular messengers to regulate the intensity and duration of immune responses by binding to receptors on target cells. There are four main structural families of cytokines - hematopoietin receptor family, interferon receptor family, TNF receptor family, and chemokine receptor family. Cytokines can act through autocrine, paracrine, or endocrine signaling and activate signaling pathways like JAK-STAT. An imbalance in the levels of cytokines produced by TH1 and TH2 cells can lead to different disease outcomes. Cytokine-related diseases include septic shock, toxic shock syndrome, and some cancers and infections.
T-cell receptors are heterodimers consisting of alpha and beta chains with variable and constant regions. The variable region binds to antigens presented by the major histocompatibility complex and contains complementary determining regions that provide specificity. While the TCR is responsible for antigen recognition, it does not signal within the cell itself. Signal transduction is carried out by the CD3 complex, which contains gamma, delta, epsilon, and zeta chains and lacks kinase activity.
- T cell and B cell progenitors undergo development in primary lymphoid organs like the thymus and bone marrow respectively, where they must pass selection checkpoints to ensure their antigen receptors are functional but not autoreactive before forming mature naive cells.
- Both cell types transduce signals through their antigen receptors (TCR and BCR) using similar pathways, but undergo different activation processes depending on the type of antigen encountered - thymus-independent versus thymus-dependent.
- B cells activated by thymus-dependent antigens can form germinal centers, where somatic hypermutation and class switch recombination refine long-term antibody responses, while thymus-independent antigens can directly induce plasm
T-cells are a type of white blood cell that play a major role in the immune system by fighting infection. There are different types of T-cells that act in various ways to identify and destroy pathogens. T-cells mature and develop in the thymus gland, where they are selected and educated to recognize the body's own cells and mount immune responses against foreign threats. T-cells recognize antigens presented on other cells through molecules of the major histocompatibility complex and are activated through a process that involves antigen presentation, costimulatory signals, and cytokine communication.
This document provides an overview of cytokines, which are proteins that mediate cell-to-cell communication during immune responses. Cytokines are secreted by white blood cells and other cells in response to stimuli. They regulate immune cell development and functions such as inflammation. Cytokines bind to specific cell surface receptors and initiate signaling pathways that regulate gene expression. The document discusses the four main families of cytokines, their properties, functions, receptors, and antagonists. It also describes how T-helper 1 and T-helper 2 cells secrete different cytokine profiles that determine the type of immune response mounted.
Lactate dehydrogenase (LDH) is an enzyme that catalyzes the conversion of lactate to pyruvate. It exists as five isoenzymes (LDH-1 to LDH-5) that differ in their subunit composition and electric charge. The isoenzymes show varying tissue distribution, catalytic properties, and clinical significance. Elevated levels of specific isoenzymes can help identify the origin of tissue damage, as LDH-1 and LDH-2 indicate myocardial infarction while LDH-4 and LDH-5 signify liver damage. The LDH isoenzyme pattern also provides information about different cancer types.
The complement system is part of the innate immune system and consists of over 30 proteins. It was originally identified in the 1890s by Jules Bordet and Paul Ehrlich as a heat-labile component of serum that enhanced the ability of antibodies to kill bacteria. There are three complement activation pathways: the classical pathway which is initiated by antibody-antigen complexes, the lectin pathway which is activated by mannose-binding lectin, and the alternative pathway which is spontaneously activated by microbial surfaces. Complement activation results in opsonization, inflammation, and formation of the membrane attack complex to kill microbes. Deficiencies in specific complement components can increase susceptibility to certain infections.
This document discusses T cell development and the mechanisms of repertoire selection and self tolerance in the thymus. It describes how T cells undergo positive and negative selection to ensure they are useful for recognizing foreign antigens while remaining tolerant to self. During positive selection in the thymus, T cells learn to recognize antigen only in the context of self MHC molecules. Negative selection removes self-reactive T cells that could cause autoimmunity. The thymus plays a key role in central tolerance and generation of a useful T cell repertoire restricted to self MHC.
immunological tolerance can be divided into two parts. they are central tolerance and peripheral tolerance. this slide contains information on development of central tolerance which include both B cell and T cell central tolerance.
B-cell maturation begins with hematopoietic stem cells in the bone marrow, where they develop through pro-B cell, pre-B cell, and immature B cell stages. During this process, immunoglobulin genes undergo rearrangement and expression of B cell receptors occurs. Immature B cells then migrate to secondary lymphoid tissues to complete maturation. Mature B cells circulate and are activated by antigen to proliferate and differentiate into plasma cells or memory B cells through T cell dependent or independent pathways. T cell dependent activation induces affinity maturation, class switching, and generation of long-lived memory B cells.
This document defines key terms related to antigens and the immune response. It discusses how antigens stimulate an immune response by interacting with antibodies and T cells. There are different types of antigens including exogenous antigens that enter the body from outside, endogenous antigens generated inside cells, autoantigens that are recognized by the immune system in autoimmune diseases, and tumor antigens expressed by cancer cells. The document also describes properties of antigens like immunogenicity and antigenicity, and characteristics of antigenic epitopes recognized by B cells and T cells. It classifies antigens as thymus-dependent or -independent and discusses conventional antigens, superantigens, and adjuvants that enhance immune responses.
Dr. Prem Mohan Jha presented on complement physiology. The complement system is part of the innate immune system and helps antibodies clear pathogens. It involves a biochemical cascade that is activated via three pathways: classical, lectin, and alternative. Complement activation leads to the formation of the membrane attack complex (MAC) which lyses cells. The complement system is tightly regulated to prevent damage to host cells. Deficiencies in complement components or regulators result in increased susceptibility to infections.
The document summarizes key aspects of T cell antigen receptor (TcR) structure and generation of diversity. It describes how TcR were discovered using monoclonal antibodies that recognize unique structures on T cell clones. TcR are heterodimers composed of α and β chains that are similar to antibody structures but do not undergo somatic hypermutation. TcR diversity is generated through combinatorial rearrangement of variable (V), diversity (D), and joining (J) gene segments, as well as junctional diversity from imprecise joining and addition of untemplated nucleotides.
B and T cell maturation involves three phases: 1) generation of antigen receptors through gene rearrangement, 2) refinement of antigen receptor repertoire through positive and negative selection, and 3) stimulation by foreign antigens. Positive selection ensures T cells recognize self MHC weakly, while negative selection eliminates those binding strongly to self antigens. The thymus tests T cells through these selection processes, with 98% of thymocytes undergoing apoptosis. Both B and T cells develop in specialized microenvironments, undergo gene rearrangement to generate diverse antigen receptors, and involve cell death via apoptosis.
The complement system consists of three pathways - the classical, lectin, and alternative pathways. The lectin pathway is activated when mannose-binding lectin (MBL) binds to mannose sugars on microbial surfaces. This binding activates MASP-1 and MASP-2, analogous to C1r and C1s in the classical pathway. MASP-1 and MASP-2 then cleave C4 and C2 to form the C3 convertase, which activates the remainder of the complement cascade. The lectin pathway thus provides an antibody-independent mechanism for complement activation in response to microbial pathogens.
The document discusses the major histocompatibility complex (MHC) in mammals. It notes that MHC acts as antigen presenting receptors and are involved in cell-cell interaction, antigen presentation, and recognition of self and non-self molecules. MHC is found on chromosome 6 in humans and is referred to as the HLA complex. MHC molecules are divided into three main classes - Class I MHC present antigens to cytotoxic T cells, Class II MHC present antigens to helper T cells, and Class III MHC genes encode complement components and cytokines. The structures and functions of Class I and Class II MHC molecules are described in detail.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
This document provides a summary of key cell surface markers (CD markers) for different immune cell types in humans and mice. It lists the main CD markers used to identify T cells, B cells, dendritic cells, NK cells, stem/precursor cells, macrophages/monocytes, granulocytes, platelets, erythrocytes, endothelial cells and epithelial cells in both species. It also provides some information on the functions of the Human Leukocyte Differentiation Antigens (HLDA) workshop which aims to standardize CD marker nomenclature.
The immunological synapse is the contact point between a T cell and antigen presenting cell where signaling and protein segregation occurs. It is composed of concentric rings called the central, peripheral, and distal supramolecular activation complexes. Signaling occurs through redistribution and segregation of receptors and proteins at the cell surface through both passive binding and active lateral movement and vesicle transport. Immunological synapses play a role in processes like HIV persistence through virological synapse formation between infected and uninfected T cells.
Cytokines are low molecular weight proteins or peptides that are important signaling molecules that regulate immunity and inflammation. They act as intercellular messengers to regulate the intensity and duration of immune responses by binding to receptors on target cells. There are four main structural families of cytokines - hematopoietin receptor family, interferon receptor family, TNF receptor family, and chemokine receptor family. Cytokines can act through autocrine, paracrine, or endocrine signaling and activate signaling pathways like JAK-STAT. An imbalance in the levels of cytokines produced by TH1 and TH2 cells can lead to different disease outcomes. Cytokine-related diseases include septic shock, toxic shock syndrome, and some cancers and infections.
T-cell receptors are heterodimers consisting of alpha and beta chains with variable and constant regions. The variable region binds to antigens presented by the major histocompatibility complex and contains complementary determining regions that provide specificity. While the TCR is responsible for antigen recognition, it does not signal within the cell itself. Signal transduction is carried out by the CD3 complex, which contains gamma, delta, epsilon, and zeta chains and lacks kinase activity.
- T cell and B cell progenitors undergo development in primary lymphoid organs like the thymus and bone marrow respectively, where they must pass selection checkpoints to ensure their antigen receptors are functional but not autoreactive before forming mature naive cells.
- Both cell types transduce signals through their antigen receptors (TCR and BCR) using similar pathways, but undergo different activation processes depending on the type of antigen encountered - thymus-independent versus thymus-dependent.
- B cells activated by thymus-dependent antigens can form germinal centers, where somatic hypermutation and class switch recombination refine long-term antibody responses, while thymus-independent antigens can directly induce plasm
T-cells are a type of white blood cell that play a major role in the immune system by fighting infection. There are different types of T-cells that act in various ways to identify and destroy pathogens. T-cells mature and develop in the thymus gland, where they are selected and educated to recognize the body's own cells and mount immune responses against foreign threats. T-cells recognize antigens presented on other cells through molecules of the major histocompatibility complex and are activated through a process that involves antigen presentation, costimulatory signals, and cytokine communication.
This document provides an overview of cytokines, which are proteins that mediate cell-to-cell communication during immune responses. Cytokines are secreted by white blood cells and other cells in response to stimuli. They regulate immune cell development and functions such as inflammation. Cytokines bind to specific cell surface receptors and initiate signaling pathways that regulate gene expression. The document discusses the four main families of cytokines, their properties, functions, receptors, and antagonists. It also describes how T-helper 1 and T-helper 2 cells secrete different cytokine profiles that determine the type of immune response mounted.
Lactate dehydrogenase (LDH) is an enzyme that catalyzes the conversion of lactate to pyruvate. It exists as five isoenzymes (LDH-1 to LDH-5) that differ in their subunit composition and electric charge. The isoenzymes show varying tissue distribution, catalytic properties, and clinical significance. Elevated levels of specific isoenzymes can help identify the origin of tissue damage, as LDH-1 and LDH-2 indicate myocardial infarction while LDH-4 and LDH-5 signify liver damage. The LDH isoenzyme pattern also provides information about different cancer types.
The complement system is part of the innate immune system and consists of over 30 proteins. It was originally identified in the 1890s by Jules Bordet and Paul Ehrlich as a heat-labile component of serum that enhanced the ability of antibodies to kill bacteria. There are three complement activation pathways: the classical pathway which is initiated by antibody-antigen complexes, the lectin pathway which is activated by mannose-binding lectin, and the alternative pathway which is spontaneously activated by microbial surfaces. Complement activation results in opsonization, inflammation, and formation of the membrane attack complex to kill microbes. Deficiencies in specific complement components can increase susceptibility to certain infections.
This document discusses T cell development and the mechanisms of repertoire selection and self tolerance in the thymus. It describes how T cells undergo positive and negative selection to ensure they are useful for recognizing foreign antigens while remaining tolerant to self. During positive selection in the thymus, T cells learn to recognize antigen only in the context of self MHC molecules. Negative selection removes self-reactive T cells that could cause autoimmunity. The thymus plays a key role in central tolerance and generation of a useful T cell repertoire restricted to self MHC.
immunological tolerance can be divided into two parts. they are central tolerance and peripheral tolerance. this slide contains information on development of central tolerance which include both B cell and T cell central tolerance.
1. T cells develop in the thymus through rearrangement of TCR genes and positive and negative selection which results in MHC restriction and self-tolerance.
2. Mature T cells express the TCR-CD3 complex and either CD4 or CD8 as co-receptors. They also express accessory molecules like CD28, CTLA-4, LFA-1 which regulate activation.
3. T cells are classified as naive or memory based on activation status, and as CD4+ T helper cells, CD8+ cytotoxic T cells, or regulatory T cells based on surface markers.
T cells mature in the thymus where they undergo positive and negative selection to ensure MHC restriction and self-tolerance. Upon activation, T cells require two signals - signal 1 through the TCR interacting with MHC-peptide and signal 2 through co-stimulatory molecules like CD28 and B7 interacting. Without co-stimulation, T cells become anergic or apoptotic. Certain antigens called superantigens can bypass normal antigen recognition and cause polyclonal activation by binding both the TCR and MHC. After activation, T cells differentiate into effector and memory populations, and activation-induced cell death regulates termination.
The development of T cells involves three main stages:
1) Gene rearrangement in the thymus produces the primary repertoire of T cell receptors.
2) Positive and negative selection act on this primary repertoire to produce mature, naive T cells that are self-tolerant but responsive to foreign antigens.
3) Mature T cells exit the thymus into secondary lymphoid tissues like lymph nodes and the spleen.
The document discusses adaptive immunity and the specific immune response. It describes how adaptive immunity provides lifelong protective immunity through antigen-specific responses that are mediated by lymphocytes, including B cells, T cells, helper T cells, and killer T cells. Lymphocytes have antigen receptors like the B cell receptor and T cell receptor that provide specificity. The adaptive immune response develops over a person's lifetime through somatic recombination and clonal selection that generates a diverse repertoire of lymphocytes each with a unique receptor.
This document summarizes key concepts about T cell maturation, activation, and differentiation from Chapter 9. It describes how T cells mature in the thymus through positive and negative selection to recognize antigen only in the context of self-MHC. The structure and role of the T cell receptor and accessory molecules like CD4, CD8, and CD3 in antigen recognition and signal transduction are also summarized. Finally, it discusses the requirements for T cell activation, including engagement of the TCR with antigen/MHC and costimulatory molecules.
This document discusses T-cell development and maturation in the thymus. It explains that progenitor T-cells migrate to the thymus where they undergo rearrangement of T-cell receptor genes. They then go through positive and negative selection processes. Positive selection ensures they can recognize self-MHC molecules, while negative selection eliminates self-reactive T-cells. This results in a T-cell repertoire that is MHC-restricted and self-tolerant. The double-positive stage is when selection occurs, determining which cells will mature into single-positive CD4 or CD8 T-cells that migrate out of the thymus.
T-cell maturation involves progenitor T cells migrating to the thymus and undergoing rearrangement of T-cell receptor genes. In the thymus, developing T cells known as thymocytes go through double negative and double positive stages where they rearrange their TCR genes and express coreceptors. Thymocytes then undergo positive and negative selection processes to ensure they are self-MHC restricted and self-tolerant before leaving the thymus as mature CD4 or CD8 T cells.
T-cell engineering involves modifying T-cells to target specific antigens through two main methods: transferring genes encoding tumor-specific T-cell receptors or engineering T-cells with chimeric antigen receptors. Chimeric antigen receptors are artificial receptors that combine the antigen recognition domain of an antibody with T-cell activating signaling domains to redirect T-cell specificity. Engineered CAR T-cell therapies show promise in treating cancers by recognizing tumor-associated antigens and triggering T-cell mediated killing of cancer cells, though they still require pre-conditioning with chemotherapy.
The document discusses major histocompatibility complexes (MHCs), which are glycoproteins found on cell surfaces that present antigen fragments to T cells. It describes MHC Class I and Class II molecules, which present antigens from intracellular and extracellular pathogens, respectively. MHC genes were first identified as important in tissue graft rejection and show high polymorphism between individuals.
The document discusses the major histocompatibility complex (MHC), which consists of glycoproteins found on cell surfaces that present antigens to T cells. MHC molecules are divided into class I and class II. Class I molecules are found on all nucleated cells and present antigens to CD8+ T cells, while class II molecules are found on antigen-presenting cells and present antigens to CD4+ T cells. The MHC was first identified as important for tissue graft compatibility.
The document discusses T lymphocytes and their generation, maturation, activation, and differentiation. It provides details on:
1) T-lymphocytes mature in the thymus gland and express T-cell receptors that recognize antigens bound to MHC molecules. They differentiate into helper T-cells, cytotoxic T-cells, memory T-cells, and regulatory T-cells.
2) T-cell receptors are composed of alpha and beta chains that undergo gene rearrangement during development.
3) T-cells mature through double negative, double positive, and single positive stages in the thymus, undergoing positive and negative selection to remove self-reactive cells.
T-cells are a type of white blood cell that play a major role in the immune system by fighting infection. There are different types of T-cells that act in various ways to identify and destroy pathogens. T-cells mature in the thymus gland, where they develop receptors called TCRs that allow them to recognize antigens bound to MHC molecules on other cells. The MHC presents antigen fragments to T-cells to trigger an immune response against invading microbes.
The adaptive immune system is composed of lymphocytes that generate a diverse repertoire of antigen receptors. T cells develop in the thymus through positive and negative selection to remove self-reactive cells. CD4+ T cells help B cells and CD8+ T cells perform cytotoxic functions by killing infected, tumor, or allograft cells via perforin/granzyme release or Fas/FasL interaction. Adaptive immunity provides tailored immune responses and immunological memory.
Lect 2 cells of immune system rmc 2016Hassan Ahmad
The document summarizes key aspects of cells of the immune system:
1. Hematopoietic stem cells in the bone marrow give rise to two main immune cell lineages - the lymphoid lineage which includes T cells, B cells, and NK cells, and the myeloid lineage which includes macrophages, dendritic cells, and granulocytes.
2. T cells develop and mature in the thymus, undergoing positive and negative selection to eliminate self-reactive cells. Mature T cells express either CD4 or CD8 and have a specific T cell receptor.
3. B cells develop and mature in the bone marrow, also undergoing selection to eliminate self-reactive cells.
The document summarizes the innate and adaptive immune system. It describes the lymphocytes (T and B cells) that are key cells of the adaptive immune system. It then focuses on T cells, describing their identification by CD molecules including CD3, CD4, and CD8. It explains the roles of CD4+ T helper cells and CD8+ cytotoxic T cells. It also briefly discusses natural killer cells and their role in killing infected and tumor cells.
T cells develop from progenitor cells in the thymus through a multi-step process involving gene rearrangement, expression of cell surface markers, and positive and negative selection. Immature thymocytes first express no cell surface markers, then either CD4 or CD8 alone, before maturing into cells that express either CD4 or CD8. Only those cells that interact with self-MHC molecules through their receptors survive positive selection, while cells reacting too strongly to self-antigens undergo negative selection. Mature naive T cells then exit the thymus to secondary lymphoid tissues and circulate in the blood until encountering their specific antigen.
Similar to T Cell Repertoire & Self Tolerance (20)
The umbilical cord connects the fetus to the placenta and measures approximately 50 cm in length and 2 cm in diameter at term. It contains one vein that carries oxygenated blood to the fetus and two arteries that carry deoxygenated blood away. The cord inserts into the placenta near its center in most cases. Abnormalities can include abnormal insertion points, short or long length, knots, torsion, hematoma, or having a single umbilical artery instead of two.
The placenta develops from fetal and maternal tissues to function as the respiratory, nutritive, excretory, barrier and endocrine organ of pregnancy. It transfers oxygen, nutrients and waste between the mother and fetus. The placenta can develop abnormalities in its shape, size, position or adhesion to the uterine wall which may cause complications like preterm birth or hemorrhage. Placental lesions like infarcts may also occur due to conditions like hypertension.
The document discusses the fetal membranes, which include the chorion and amnion. The chorion is the outer membrane that is attached to the placenta and uterine wall. The amnion lines the chorion and encloses the fetus and amniotic fluid. The amniotic fluid provides protection and nutrition for the fetus, and aids in temperature regulation and movement. It is composed primarily of water, carbohydrates, proteins and minerals. The amniotic fluid circulates continuously, with production from the fetal membranes, fetal urine and transudation from maternal and fetal blood.
The document summarizes the key stages in human reproduction from fertilization through early pregnancy development. It describes how sperm mature and are capacitated in the female reproductive tract. Upon ovulation, sperm meet and fertilize the ovum in the fallopian tubes. The zygote then undergoes cell division and develops into a blastocyst that implants in the uterus. The trophoblast cells of the blastocyst invade the uterine lining and develop into a placenta to exchange nutrients and waste with the mother's blood. Major developmental milestones in early pregnancy include chorion, amnion and decidua formation.
The document discusses several minor complaints that may occur during pregnancy, including gingivitis, ptyalism, heartburn, constipation, hemorrhoids, varicosities, dyspnea, urinary symptoms, leucorrhea, leg cramps, paraethesia, and backache. For each complaint, the causes and recommended treatments are provided.
This document discusses the diagnosis of pregnancy over three trimesters. In the first trimester, common symptoms include missed periods, morning sickness, frequent urination, and breast changes. Signs include enlarged, soft breasts and uterus, and a softer, purplish cervix. Pregnancy tests detect human chorionic gonadotropin in urine or blood. Ultrasounds can visualize the gestational sac after 4-5 weeks. In the second trimester, symptoms decrease while the abdomen enlarges and fetal movement is felt. Signs include skin changes and palpable fetal parts. The third trimester confirms pregnancy through palpation of fetal parts and auscultation of the fetal heart.
Antenatal care involves regular checkups during pregnancy to monitor the health of the mother and baby. Checkups include exams, tests, and education on nutrition, exercise, hygiene, warning signs and avoiding risks. The goals are to prevent or treat complications, detect issues, and ensure healthy development. Women receive more frequent exams as their due date approaches, and are instructed on a nutritious diet, moderate exercise, adequate rest, hygienic practices, and when to seek medical help if problems arise.
The document discusses postpartum mood disorders, including prevalence, risk factors, screening tools, diagnosis, and treatment options. It notes that postpartum mood disorders range from mild and temporary postpartum blues to more severe postpartum depression and postpartum psychosis. Screening tools like the Edinburgh Postnatal Depression Scale can help identify at-risk women. Treatment involves psychosocial therapies and may include antidepressant medication depending on severity. A multidisciplinary approach is important to address biological, psychological and social factors.
Uterine fibroids are benign smooth muscle tumors that develop in the uterus. They are the most common solid pelvic tumors, affecting 20-25% of women during their reproductive years. Fibroids can vary in size and location, and may cause heavy menstrual bleeding, pelvic pressure or pain. Treatment options include observation, medical therapy to reduce estrogen levels, or surgical removal of fibroids.
Version refers to changing the fetal lie or position in the uterus. There are three main types: external cephalic version, internal podalic version, and bipolar podalic version. External cephalic version involves manipulating the fetus externally to convert a breech presentation to head-first. Internal podalic version is performed under anesthesia when the cervix is fully dilated to grasp the fetus's feet and convert a transverse lie to breech. Bipolar podalic version uses both internal and external manipulation through a partially dilated cervix for special circumstances. Complications can include fetal distress, premature separation of the placenta, and maternal hemorrhage.
Vacuum extraction is a method to assist in childbirth using suction from a cup placed on the baby's head to help with traction during contractions. There are different types of cups including metal, soft, and bird's cups. Vacuum extraction is indicated when forceps cannot be used and has advantages over forceps like less need for anesthesia and less compression force applied. Complications can include maternal lacerations and cervical injuries or fetal issues like cephalhematomas and scalp lacerations.
Symphysiotomy is a surgical procedure that divides the symphysis pubis bone to widen the pelvis during childbirth. It is indicated when cephalopelvic disproportion makes vaginal delivery difficult or dangerous but cesarean section is not available or advised. The procedure involves making a small incision above the pubic bone and gradually separating the joint using a scalpel. Complications can include bleeding, injury to nearby organs, infection, and long-term issues like incontinence or an unstable pelvis.
This document discusses obstetric forceps, which are metal instruments used to extract a baby's head during delivery. It describes different types of forceps and their proper application techniques. Forceps are indicated for prolonged second stage of labor, maternal distress, or fetal distress. Correct application involves inserting one blade along each side of the baby's head. Potential complications include laceration, hemorrhage, nerve injury, or problems for the baby such as skull fractures. Failure to deliver with forceps may require removal and assessment to determine if cesarean section is needed.
This document discusses episiotomy, which is an incision made in the perineum during childbirth to widen the vaginal opening. It can help prevent tearing and complications. The two main types are median and mediolateral episiotomies. Median episiotomies involve a midline incision while mediolateral incisions extend laterally towards the ischial tuberosity. Episiotomies are usually performed when the vaginal opening is distended during crowning to prevent stretching injuries. They are sutured closed after delivery.
The document discusses Caesarean section, including indications, types, procedure, complications, and mode of delivery in subsequent pregnancies. A Caesarean section is a surgical procedure to deliver one or more babies through incisions in the abdomen and uterus. The rate of Caesarean sections has increased from 5% in 1970 to 25% in 1990 due to factors such as abandoning difficult procedures in favor of C-sections and increased use for breech births. Complications can include hemorrhage, infections, and injuries to the mother or baby.
Normal labour involves the spontaneous expulsion of a single, mature fetus through the birth canal within 3-18 hours without complications. It occurs when hormonal and mechanical factors cause the cervix to efface and dilate in stages from 3cm to full 10cm dilation. Labour proceeds through four stages: 1) cervical dilation, 2) expulsion of the fetus, 3) expulsion of the placenta, and 4) recovery. The fetus descends through the birth canal with increased flexion to facilitate delivery of the head.
The fetal skull consists of three parts: the vault, face, and base. The vault is made up of the frontal, parietal, and occipital bones which are separated by sutures. The face extends from the chin to the nose. Fontanelles are soft spots located where sutures meet which are important for assessing fetal position and flexion. The skull has various longitudinal and transverse diameters used to determine which will engage and pass through the birth canal during delivery.
The female pelvis is divided into the false pelvis and true pelvis. The true pelvis is further divided into the pelvic inlet, cavity, and outlet. The document describes the boundaries and diameters of each region including the anatomical transverse diameter of 13cm at the inlet. It also discusses the pelvic planes and axes, and the Caldwell-Moloy classification of pelvic types including the gynaecoid, anthropoid, android, and platypelloid pelvis.
This document outlines the active management of normal labour in 4 stages: antenatal preparation, first stage (history, exam, procedures), second stage (delivery of baby), third stage (delivery of placenta), and fourth stage (postpartum care of mother and baby). The goal is a healthy delivery with minimal effects. Key procedures include monitoring contractions/fetal heart with a partogram, positioning, nutrition, analgesia, perineal support, and immediate newborn care.
Thyrotoxicosis in pregnancy can cause complications like abortion and preterm labour. Clinical features include weight loss, heat intolerance, tremors, and fast heart rate. It is treated with antithyroid drugs like propylthiouracil or carbimazole. Epilepsy in pregnancy commonly presents as grand mal seizures, which are treated with phenobarbitone or phenytoin along with folic acid. Rhesus isoimmunization occurs when an Rh-negative mother develops antibodies against Rh-positive blood from her baby. It can be prevented by giving the mother anti-D immunoglobulin after delivery or pregnancy events involving blood transfer from baby to mother. Affected babies may require monitoring, phot
2. Why is a mechanism for repertoire selection and self tolerance needed? Generation of the TcR repertoire involves many random mechanisms The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are: T T T T T T T T T T T T T T T T T T T T T T T T T 2. Useless T T T APC 3. Useful Foreign antigen recognition T 1. Harmful Self antigen recognition
3. Self proteins enter the endogenous and exogenous antigen processing pathways Processing pathways do not distinguish self from non-self Self cellular proteins Self serum & cellular proteins
4. >90% of eluted peptides are derived from self proteins Yet self antigens do not usually activate T cells Self peptides load onto MHC class I & II molecules Purify stable MHC-peptide complexes Fractionate and microsequence peptides Acid elute peptides
5. TcRs recognise the non-self peptide antigen and the self MHC molecule MHC molecules RESTRICT T cell activation But how do T cells learn how much self recognition is acceptable? The immune system allows a limited degree of self recognition
6. T cells are only allowed to develop if their TcR recognise parts of self MHC MHC A haplotype T CELL Explains why T cells of MHC haplotype A do not recognise antigen specific presented by MHC haplotype B MHC B haplotype APC MHC A haplotype APC
7. Harmful Useless Useful Positively select Negatively select Wholly self-reactive and useless T cells are removed MHC-restricted are retained THYMUS Neglect Y T Y Y T T APC Y T ? Y T Y T Y Y Y Y T T Y Y T T Y Y Y T T T Y Y Y Y T Y T T T Random TcR repertoire ensures diversity Y T Y T Y T
8. The thymus Lobulated structure with a STROMA of epithelial cells & connective tissue Stroma provides a microenvironment for T cell development & selection Lobules differentiated into an outer CORTEX & inner MEDULLA , both filled with bone-marrow-derived THYMOCYTES Cortex Medulla Cortical epithelial cell Medullary epithelial cell Dendritic cell Thymocyte Macrophage
9. The thymus is required for T cell maturation Athymic mice ( nude ) and humans (DiGeorge syndrome) are immunodeficient due to a lack of T cells Neonatal thymectomy No mature T cells In adult Thymus intact Mature T cells In adult
10. Roles of the bone marrow and thymus in T cell maturation Defective lymphocyte production Normal thymus scid/scid Thymus defect Normal bone marrow nu/nu No mature T cells In adults No mature T cells In adults
11. Bone marrow supplies T cells, and they mature in the thymus Thymus colonised by thymocytes from the thymus defective, i.e. orange, mouse Thymus graft Bone marrow transplant Thymus colonised by thymocytes from thymus defective, i.e. orange, mouse Marrow defect Thymus defect
12. The thymus matures T cells after birth, but early in life Remove Thymus Mature T & B cells No T cells Mature B cells present T cells not yet left thymus The thymus is needed to generate mature T cells Adult Neonate
13. The thymus is most active in the foetal and neonatal period The thymus is needed for NEONATAL TOLERANCE T cells vs. OVA Adult Neonate No T cells vs.OVA OVA KLH T cells vs. KLH T cells vs. KLH
14. T cells mature in the thymus but most die there. 98% of cells die in the thymus without inducing any inflammation or any change in the size of the thymus. Thymic macrophages phagocytose apoptotic thymocytes. Constant 1-2 x 10 8 cells Mouse thymus 5 x 10 7 per day 2 x 10 6 per day
15. T cell development is marked by cell surface molecule changes As T cells mature in the thymus they change their expression of TcR-associated molecules and co-receptors. These changes can be used as markers of their stage of maturation 98% CD3/TcR- CD4-, 8- Double negative CD3+ TcR -chain + pre-TcR + (pT CD4+, 8+ Large double positive CD3+ TcR + CD4+ CD8+ Small double positive TcR+ CD3+ CD4-, 8- CD3+ TcR + CD4+ Single positive CD3+ TcR + CD8+ Single positive
16. Different developmental stages of thymocytes are present in different parts of the thymus Cortex Immature double negative & positive thymocytes Medulla Mature single positive thymocytes DP CD3+ pT : DN CD3+ pT : CD25-, CD44- DP CD3+ TcR + DN CD25+ CD44+ DN CD25- CD44+ DN CD25+, CD44low SP CD3+ TcR + CD8+ CD3+ TcR + CD4+ SP
17. TcR rearrangement C region spliced to VDJ fusion and -chain protein produced in cytoplasm No TcR at cell surface DN CD25+, CD44low V D J C Germline configuration V D J C D-J fusion DN CD25+ CD44+ DN CD25- CD44+ V D J C V-DJ fusion
18.
19. 1. Cell proliferates rapidly to yield daughter cells with the same chain Expands only cells with in-frame TcR chains 2. Successful rearrangement shuts off rearrangement on 2nd chromosome Ensures only one specificity of TcR expressed per cell Similarities in the development of T and B cells: Pre T cell receptor DN CD3+ very low pT : CD25- CD44- TcR -chain preTcR -chain TcR -chain preTcR -chain CD8 CD4 DP CD3+ low pT : CD25- CD44- CD4+ CD8+
20. TcR rearrangement When proliferation stops, the chain starts to rearrange Germline TcR J C V V-J rearranged TcR 1° transcript Spliced TcR mRNA CD3+ TcR + DP T cells can now recognise antigens and interact with MHC class I & II through CD4 & CD8 Selection can now begin DP CD3+ low pT : CD25- CD44- CD4+ CD8+
21. How does the thymus choose which of the cells entering the thymus are useful, harmful and useless Mouse thymus 5 x 10 7 per day 2 x 10 6 per day
22. Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC i.e. selection of the USEFUL Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC or that have no affinity for self MHC i.e. selection of the HARMFUL and the USELESS Sorting the useful from the harmful and the useless Positive selection Negative selection
23. MHC restriction Antigen can be seen by the TcR only in the context of an MHC molecule TcR will not bind to an MHC molecule unless there is an antigen in the groove In the presence of antigen, the TcR must have some affinity for the MHC molecule
24. Thymus defect Marrow defect Experimental evidence for MHC restriction as a marker of positive selection CHIMERA Orange strain cells in a blue strain mouse Which MHC haplotype will restrict the T cells, Orange or blue ? Bone marrow transplant Transplant reconstitutes marrow defective mouse
25. Studies in bone marrow chimeras show that MHC restriction is learnt in the thymus T cell response of recipient T cells to antigen The MHC haplotype of the environment in which T cells mature determines their MHC restriction element Irradated bone marrow recipients MHC A MHC (AxB)F1 Bone marrow donor MHC (AxB)F1 MHC haplotype of APC A B A B A B MHC B
26. Explanation of bone marrow chimera experiment: Mice of a particular MHC haplotype only make T cells restricted by that haplotype MHC (AxB)F1 Able to make T cells restricted by MHC A or B MHC A Able to make T cells restricted by MHC A MHC B Able to make T cells restricted by MHC B Bone marrow must contain potential to make T cells restricted by A and B MHC molecules
27. Explanation of bone marrow chimera experiment: Irradiation prevents the bone marrow from generating lymphocytes These mice are severely immunodeficient and can only be reconstituted by a bone marrow transplant Irradiation destroys the immune system but has no effect on the epithelial or dendritic cells of the thymus MHC A MHC B MHC A MHC B Normal mice MHC A MHC B Mice now have an intact, functional thymic stroma but have no thymocytes, T cells or bone marrow
28. Bone marrow contains the potential to make T cells restricted by A and B MHC molecules Explanation of bone marrow chimera experiment: Reconstitution of irradiated mice with (AxB)F1 bone marrow MHC (AxB)F1 MHC A MHC (AxB)F1 MHC B Irradiated bone marrow recipients Transplant bone marrow to reconstitute immune system of immunodeficient mice
29. Mouse with an MHC A thymus, but A x B bone marrow Mouse with an MHC B thymus, but A x B bone marrow Explanation of bone marrow chimera experiment: MHC restriction is learnt in the thymus by positive selection Mature T cells restricted only by MHC A Mature T cells restricted only by MHC B A x B T cell precursors MHC A Thymus A x B T cell precursors MHC B Thymus
30. MHC haplotype of antigen presenting cells Explanation of bone marrow chimera experiment: Peripheral T cells are restricted by the MHC type of the thymus that they mature in MHC (AxB)F1 Bone marrow donor T cell response of recipient T cells to antigen A B A B MHC A MHC B Bone marrow recipients
31. T cells are ‘educated’ in the thymus to recognise antigens only in the context of self MHC The MHC haplotype of the environment in which T cells mature determines their MHC restriction element Bone marrow chimeras show that MHC restriction is learnt in the thymus Summary MHC restriction is learnt in the thymus by positive selection
32. Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC or that have no affinity for self MHC i.e. selection of the HARMFUL and the USELESS Negative Selection Superantigens can be used to probe the mechanisms of negative selection
33. Nominal antigens & superantigens Nominal antigens Require processing to peptides TcR and chains are involved in recognition >1 in 10 5 T cells recognise each peptide Recognition restricted by an MHC class I or II molecule Almost all proteins can be nominal antigens Superantigens Not processed Only TcR chain involved in recognition 2-20% of T cells recognise each superantigen Presented by almost any MHC class II molecule Very few antigens are superantigens Suggests a strikingly different mechanism of antigen presentation & recognition.
34. Superantigens e.g. Staphylococcal enterotoxins Toxic shock syndrome toxin I (TSST-1) Staphylococcal enterotoxins SEA, SEB, SEC, SED & SEE Do not induce adaptive responses, but trigger a massive burst of cytokines that may cause fever, systemic toxicity & immune suppression Severe food poisoning Toxic shock syndrome Class II from MHC A to Z haplotypes TcR from MHC A haplotype T cell APC V V
35. Interaction of SEB with MHC Class II molecules and the TcR MHC class II TcR beta chain MHC class II SEB TcR beta chain SEB
36. Exogenous superantigen-V relationship Superantigen Human V region SEA 1.1, 5.3, 6.3, 6.4 6.9, 7.3, 7.4, 9.1 SEB 3, 12, 14, 15, 17, 20 SEC 1 12 SEC 2 12, 13.1, 13.2 SED 5, 12 SEE 5.1, 6.3, 6.4, 6.9, 8.1 TSST-1 2 Explains why superantigens stimulate so many T cells
37. Effect of TSST-1 on T cells expressing V 2 Fresh PBMC stained with anti-V 2 PBMC cultured with TSST-1 Stained with anti-V 3 Fresh PBMC unstained Fluorescence intensity (i.e. amount of staining with anti-V antibody) Cell number PBMC cultured with TSST-1 Stained with anti-V 2 Cell number
38. Other exogenous superantigens Bacterial exoproteins Staphylococcal exfoliative toxins Streptococcus pyogenes erythrogenic toxins A & C (?Streptococcal M protein?) Yersinia enterocolitica superantigen Clostridium perfingens superantigen Mycoplasma arthritidis mitogen
39. Superantigens Mouse mammary tumour viruses (Mtv) Cell-tethered superantigen encoded by the viral genome TcR from MHC A haplotype T cell APC Class II from MHC A to Z haplotypes Vb V V
40. Endogenous superantigens Mouse mammary tumour viruses (MMTV) Retroviruses that contain an open reading frame in a 3’ long terminal repeat that encodes a superantigen associated with the cell surface of APC Most mice carry 2-8 integrated MMTV proviruses in their genome Integrated MMTV Mtv-1, 2, 3, 6, 7 (Mls-1 a ), 8, 9, 11, 13 & 43 Infectious and transmitted by milk MMTV (C3H) MMTV (SW) MMTV (GR)
41. Mtv Murine V region Mtv 8 11 Mtv 11 11 Mtv 9 5.1, 5.2, 11 Mtv 6 3, 5.1, 5.2 Mtv 1 3 Mtv 3 3 Mtv 13 3 Mtv 7 6, 7, 8.1, 9 MMTV SW 6, 7, 8.1, 9 MMTV C3H 14 MMTV GR 14 Endogenous superantigen V -relationship Stimulate T cells in a similar manner to exogenous supernatigens Valuable tools in analysis of self tolerance
42. Irradiated Mtv-7 superantigen APC T Only T cells with TcR containing V 6, V 8.1 and V 9 proliferate Mtv-7 interacts with V 6, V 8.1 and V 9 and activates only cells bearing those TcR Selective expansion of cells bearing certain V chains Mtv act in a similar manner to exogenous superantigens in vitro T T T T T T T STIMULATOR CELLS Mtv-7 +ve RESPONDING T CELLS Mtv-7 -ve
43.
44. 1. MMTV infected, MHC class II positive B cells Transmission of infection B T 2. Massive T cell response to MMTV superantigen 3. Vigorous T cell help leads to B cell proliferation and differentiation to long-lived B cells 4. Infected cells traffic to mammary gland and infect young via milk
45. Analysis of negative selection in vivo. Mtv Mtv-7 superantigen binds to V 6, V 8.1 and V 9+ve thymocytes Mtv-7 superantigen positive Negative selection Immature CD4+8+ thymocytes expressing V V 8.1 and V 9 in the thymus No mature CD4+ or CD8+ V V 8.1 and V 9 T cells in periphery Mtv-7 superantigen negative Immature CD4+8+ thymocytes expressing V V 8.1 and V 9 in the thymus Negative selection Mature CD4+ or CD8+ V V 8.1 and V 9 T cells in periphery THYMUS PERIPHERY
46. Analysis of negative selection in vivo. Milk transmissible superantigens - MMTV (C3H) V 14 present? Yes No Male or female B10.BR Male or female C3H
47. No X Male C3H Female B10.BR V 14 present? F1 offspring Male B10.BR Female C3H X V 14 present? F1 offspring Yes
48. No Deletion of V 14 T cells in mice infected with MMTV by milk MMTV transmitted to fostered pups by infected B cells found in milk + Foster female B10.BR Young male or female C3H Yes V 14 present in fostered pups? + Foster female C3H Young male or female C3H Or B10.BR
49. Are the signals that induce positive & negative selection the same, or different? Negative selection Peripheral T cells SAME specificity DIFFERENT specificity Positive selection Immature thymocytes X T H Y M U S
50. Hypotheses of self-tolerance Avidity hypothesis Affinity of the interaction between TcR & MHC Density of the MHC:peptide complex on the cell surface Quantitative difference in signal to thymocyte. Differential signalling hypothesis Type of signal that the TcR delivers to the cell Qualitative difference in signal to thymocyte.
51. Removal of useless cells Peptide is not recognised or irrelevant Thymocyte receives no signal, fails to be positively selected and dies by apoptosis. WEAK OR NO SIGNAL CD8 TcR T cell Thymic epithelial cell MHC Class I
52. Positive selection Peptide is a partial agonist Thymocyte receives a partial signal and is rescued from apoptosis i.e. the cell is positively selected to survive and mature. PARTIAL SIGNAL Thymic epithelial cell MHC Class I CD8 TcR T cell
53. Negative selection Peptide is an agonist Thymocyte receives a powerful signal and undergoes apoptosis i.e. the cell is negatively selected and dies. FULL SIGNAL Thymic epithelial cell MHC Class I CD8 CD8 TcR T cell
54. The thymus accepts T cells that fall into a narrow window of affinity for MHC molecules Number of cells Affinity of TcR/MHC interaction Low High Useless Neglect Useful Positively select Harmful Negatively select
56. How accurate are these models of positive and negative selection? Positive selection: Relied on very complex chimera experiments Relied on proof of MHC restriction as an outcome which is tested in an ‘unnatural’ response using MHC mismatched presenting cells Negative selection: Relied on exceptionally powerful superantigens operating outside the normal mechanisms of antigen recognition
57. Illustration of selection using TcR transgenic mice Generation of transgenic mice In TcR transgene-expressing mice almost all thymocytes express the transgenic TcR due to ALLELIC EXCLUSION . T T cell clone with known TcR specificity and MHC restriction Rearranged chain cDNA construct Rearranged chain cDNA construct } Inject into fertilised mouse ovum Re-implant Analyse offspring for transgene expression.
58. Cells that fail positive selection die in the thymus (neglect) Thymocytes die at the double positive stage after failing +ve selection due to a lack of MHC A In TcR transgenic mice expressing an MHC A restricted TcR, all thymocytes express the MHC A restricted TcR Transgenically express MHC A restricted TcR in an MHC B mouse DP CD3+ TcR + No single +ve cells are present in the periphery SP CD3+ TcR + CD8+ or CD4+ DN CD3- MHC B
59. Positive selection determines the restriction element of the TcR AND the expression of CD4 or CD8 Restriction element and co-receptor expression are co-ordinated Instructive model: Signal from CD4 silences the CD8 expression & vice versa? Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene, then test for matching of TcR restriction with co-receptor expression? TcR transgenic mouse TcR from MHC class I- restricted T cell TcR transgenic mouse TcR from MHC class II- restricted T cell Only CD8 cells mature Only CD4 cells mature
60. Instructive model: Signal from CD4 silences the CD8 expression & vice versa Double positive thymocyte Thymic epithelial cell Double positive to single positive transition Single CD4+ thymocyte X √ CD8 MHC Class I MHC Class II 3 2 TcR TcR CD4 MHC Class II 2 TcR CD4 MHC Class I 3 TcR -ve CD8
61. Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene, whilst testing a match of TcR restriction Double positive thymocyte Thymic epithelial cell Single CD4+ thymocyte Double positive to single positive transition X √ MHC Class II 2 TcR MHC Class I 3 TcR CD8 MHC Class I MHC Class II 3 2 TcR TcR CD4 CD4 CD8 CD4 CD8 CD4
62. Deletion of cells in the thymus: differential effect on the mature and immature repertoire TcR from T cell specific for hen egg lysosyme (HEL) ~100% of T cells/thymocytes express anti-HEL TcR Immunise with HEL Thymocytes activated by antigen in the thymic environment die T cells activated by antigen in the periphery proliferate TcR transgenic mouse Analyse peripheral T cells: All transgenic T cells proliferate Analyse thymus: All transgenic T cells die by apoptosis
63. How can the thymus express all self antigens – including self antigens only made by specialised tissues? How do we become self tolerant to these antigens?
67. T helper cells costimulate B cells Two - signal models of activation Y Y Y B T cell antigen receptor Co-receptor (CD4) CD40 Ligand (CD154) Th Signal 2 - T cell help CD40 MHC class II and peptide Signal 1 antigen & antigen receptor ACTIVATION
68. Antigen presentation - T cells are co-stimulated Costimulatory molecules are expressed by most APC including dendritic cells, monocytes, macrophages, B cells etc., but not by cells that have no immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc. APC Th Signal 1 antigen & antigen receptor Signal 2 B7 family members (CD80 & CD86) CD28 ACTIVATION
69. Express IL-2 receptor- and chains but no chain or IL-2 Mechanism of co-stimulation in T cells Signal 1 NFAT binds to the promoter of of the chain gene of the IL-2 receptor. The chain converts the IL-2R to a high affinity form Resting T cells Low affinity IL-2 receptor IL-2 IL-2R IL-2 IL-2R 1 Antigen
70. Signal 2 Activates AP-1 and NF -B to increase IL-2 gene transcription by 3 fold Stabilises and increases the half-life of IL-2 mRNA by 20-30 fold IL-2 production increased by 100 fold overall Mechanism of co-stimulation in T cells Immunosuppressive drugs illustrate the importance of IL-2 in immune responses Cyclosporin & FK506 inhibit IL-2 by disrupting TcR signalling Rapamycin inhibits IL-2R signalling IL-2 IL-2R 1 Antigen 2 Costimulation
71. Signal 1 only Anergy The T cell is unable to produce IL-2 and therefore is unable to proliferate or be clonally selected. Unlike immunosupressive drugs that inhibit ALL specificities of T cell, signal 1 in the absence of signal 2 causes antigen specificT cell unresponsiveness. Self peptide epitopes presented by a non-classical APC e.g. an epithelial cell IL-2 IL-2R 1 Antigen Epithelial cell Naïve T cell
72. Arming of effector T cells Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector function, but….. the T cell will be activated to proliferate and differentiate under the control of autocrine IL-2 to an effector T cell. These T cells are ARMED APC T IL-2 Effector T cell Clonal selection and differentiation How can this cell give help to, or kill cells, that express low levels of B7 family costimulators?
73. Clonally selected, proliferating and differentiated T cell i.e. ARMED sees antigen on a B7 -ve epithelial cell The effector programme of the T cell is activated without costimulation This contrasts the situation with naïve T cells, which are anergised without costimulation Effector function or Anergy? Armed Effector T cell CD28 Co-receptor TcR IL-2 Epithelial cell Naïve T cell Epithelial cell Epithelial cell Armed Effector T cell Kill
74. CD28 cross linked by B7 Costimulatory molecules also associate with inhibitory receptors CTLA-4 binds CD28 with a higher affinity than B7 molecules Co-stimulation induces CTLA-4 The lack of signal 2 to the T cell shuts down the T cell response. CD28lo Activated T cell CTLA-4hi B7 CD28 T cell B7 2 2 Signal 1 + Cross-linking of CTLA-4 by B7 inhibits co-stimulation and inhibits T cell activation - - - - -
75. The danger hypothesis & co-stimulation Fuchs & Matzinger 1995 Full expression of T cell function and self tolerance depends upon when and where co-stimulatory molecules are expressed. Innocuous challenge to the immune system fails to activate APC and fails to activate the immune system Apoptotic cell death. A natural, often useful cell death. APC APC No danger No danger Cell containing only self antigens
76. The danger hypothesis APC that detect ‘danger’ signals express costimulatory molecules, activate T cells and the immune response APC APC Necrotic cell death e.g. tissue damage, virus infection etc Pathogens recognised by microbial patterns DANGER