Describes the basic properties and mechanisms of T cells and B cells in maintaining Immune Response against foreign antigens or infections and covers the UG and PG portion of immunology.
2. Introduction
ī§ Immune response refers to the highly coordinated reaction of the cells of the
immune system and their products. It has 2 armsī
īļHumoral or Antibody mediated immune response (AMI)ī
ī§ It provides protection to the host by secreting antibodies that can bind to the
microbial antigens that are circulating or present on the cell surface and
neutralize them.
ī§ No role against intracellular antigens.
īļCell mediate immunity (CMI)ī
ī§ Crucial role in providing protection against intracellular microbes as well as
tumors.
ī§ Although, CMI is mainly T-cell mediated but other components like NK
cells, macrophages, granulocytes are also important.
5. Introduction
ī§ CMI and AMI are interdependent-
ī§ They donât work independently but are highly dependent on each other.
ī§ Cytokines released from T cells stimulate B-cells to produce antibodies.
ī§ Many effector cells of CMI like Macrophages and NK cells use antibodies
to recognize the target cells for killing.
ī§ CMI regulates HMI by regulating transformation of B-cells into antibody
secreting plasma cells.
ī§ There are certain initial events that takes places before induction of either
CMI or AMI.
ī§ These events occur irrespective of the type of immune response that will
follow.
6. Antigen presentation to
Helper T-cells
Activation and Differentiation of
Helper T-cells into TH1 or TH2 subsets
TH1 cellsī secret
Cytokinesī CMI
TH2 cellsī secret Cytokines
ī HMI
TH1 Cytokines and their functionsī
īļIL2
īą Promotes activation of TH and TC cells.
īą Activates NK cells to become LAK cells
(Lymphokine
Activated killer cells)
īļINF-đ¸
īą Activates the resting macrophages to activated
Macrophages
īą Activates B cells to produce IgG.
īą Delayed type of Hypersensitivity.
īą Inhibits TH2 cell proliferation.
īļ TNF-đˇ
īą Enhances phagocytic activity of Macrophages.
TH2 Cytokines and their functionsī
īļIL-4
īą Inhibits TH1 cells differentiation.
īą Stimulates B cells to produce IgE and IgG-1
&4.
īļIL-5
īą Enhances the proliferation of Eosinophils.
īą IL-4&5- protection against Helminthic
Infections and mediate Allergic Reactions.
īļIL-6
īą B-cell proliferation and Antibody production
īļIL-10
īą Inhibits TH1 differentiation.
7.
8. Interactions between the innate and acquired immune
systems in response to bacterial infection of the skin.
ī§ In response to bacteria that have breached the epithelial barrierī
ī§ Keratinocytes synthesize anti-microbial peptides, chemokines, and
cytokines.
ī§ These factors lead to activation of the dermal endothelium, inducing
the migration of innate leukocytes and memory T cells into the skin
and additionally guiding these cells via chemotactic gradients.
ī§ These factors and bacterial antigens activate innate phagocytes to kill
ingested organisms and activate dendritic cells to migrate to the
skin-homing lymph nodes.
9. Interactions between the innate and acquired immune
systems in response to bacterial infection of the skin.
ī§ In the lymph nodes, dendritic cells present bacterial antigens to
naŨve and central memory T cells, leading to stimulation of
pathogen-specific cells.
ī§ Effector CD8 cells exit the lymph node, home to inflamed skin and
kill pathogens.
ī§ Helper CD4 T cells provide help to B cells, inducing the production
of antibodies that directly neutralize pathogens and lead to additional
targeting of innate responses.
ī§ Antibody-directed phagocytosis by innate cells leads to enhanced
antigen presentation, further enhancing acquired responses.
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11.
12. Cluster of differentiation in helper T cell
ī§ The helper T cells can be Th1, Th2, Th9, Th17, or Th22 cells, depending
upon the pathogen and types of cytokines present in the cellular
microenvironment.
ī§ They are responsible for responding to both intracellular as well as
extracellular pathogens and have also been found to be involved in various
diseases.
ī§ CD4 T helper (Th) cells play a central role in orchestrating adaptive
immune responses to invading pathogens through their ability to
differentiate into specialized effector subsets.
ī§ Part of this customized response requires the development of T follicular
helper (Tfh) cells, which provide help to B cells for the generation of
Germinal Centers (GCs) and long-term protective humoral responses.
13. Cluster of differentiation in helper T cell
ī§ CD4 T helper cells are the primary orchestrators of the adaptive
immune response, mediating a variety of cellular and humoral
responses against pathogens and cancer.
ī§ Although they lack any capacity to directly kill or engulf pathogens,
they are powerful activators of effector cells such as macrophages,
cytotoxic T cells, and B cells.
ī§ On the other hand, Regulatory T cells (Tregs) are potent suppressors
of the immune response important in limiting the immune reaction.
ī§ Recent advances have led to the discovery of a diverse set of T helper
subsets, each with unique functions.
17. Antigen Presentationī
Antigen Presenting Cells (APCs)
ī§ For induction of immune responses, recognition of antigens by T-cells is essential.
ī§ T cells canât recognize the native and free antigens, but can do so only after antigen is
processed into smaller antigenic peptides containing specific epitopes which are
subsequently combined with MHC molecules (Class -1 /2) and presented on the host cell
surface.
ī§ Antigen presentation means the presentation of antigenic peptide to both TH (Helper T
cell) and TC (Cytotoxic T cells) by complexing with MHC class 2 and class 1 respectively.
ī§ However, APCs in strict sense refers to only only those cells (e.g, Dendritic cells, Macrophages
etc.) that present antigenic peptides to TH cells.
ī§ Virus infected cells or Tumor cells presents antigenic peptides to TC cells leading to their
activation and they arenât considered as APCs rather termed as âTarget cellsâ.
ī§ Professional APCs- Dendritic Cells, Macrophages, B-cells.
ī§ Non-Professional APCs- Fibroblasts (Skin), Endothelial cells (vessels), Glial cells (Brain).
18. Antigen Presentationī
Antigen Presenting Pathways
âĸ For induction of immune response the the antigens must be presented to TH
cells and also to TC cells. Two well defined pathways are used for this
purposeī
īļCytosolic Pathway-
ī§ Here, the endogenous (i.e. Intracellular) antigens such as Viral or tumor
antigens are processed and presented along MHC Class 1 molecules to
CD8 T cells.
īļEndocytic pathway-
ī§ The exogenous antigens (extracellular microbes and their products like
toxins) are processed and complexed with MHC class 2 molecules and
presented to TH Cells.
ī§ Professional APCs are mostly involved in this pathway.
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23. Cell Mediated Immune Response (CMI)
ī§ CMI refers to the destruction of cells carrying intracellular microbes and other
abnormal cells, such as tumor cells by various specific and non-specific cells of
immune system, of which the most important is the cytotoxic T cells.
īļRole of CMI-
īFor obligate intracellular organisms like Mycobacteria, Chlamydia, Rickettsia,
plasmodium, leishmania etc. CMI remains the only effective immune response.
īFor facultative intracellular organisms like Listeria, Salmonella, Yersinia and
Fungi such as Histoplasma and Cryptococcus, CMI becomes the leading immune
response once the organism goes intracellular from extracellular.
īProvides immunity against tumor and damaged or altered cells.
īMediates Type-4 Hypersensitivity.
24. Cell Mediated Immune Response (CMI)-
Effector Cells
ī§ CMI can be mediated by both Antigen specific and non-specific
effector cells. They perform their function by direct killing of the
target cells.
ī§ Antigen specific- Cytotoxic T cells (Most important)
ī§ Non-specific â NK Cells, Macrophages, Neutrophils, Eosinophils.
ī§ CMI is interdependent on HMI as non specific effector cells use
Antibodies for their killing (ADCC- Antibody Dependent Cell
Mediated Cytotoxicity).
25. T cell stimulation and polarization require
four signals from dendritic cells
26. īļSignal oneī determines antigen specificity
and consists of interaction of the T cell receptor
(TCR) with peptides loaded onto dendritic cell
major histocompatibility (MHC) molecules.
īļSignal twoī consists of co-signaling and can
be either positive, leading to cell activation (co-
stimulation) or negative, leading to no response
(co-inhibition).
īļ Co-signaling molecules, including CD80 and
CD86, are upregulated on dendritic cells after
binding of pathogen-associated molecular patterns
(PAMP) to their cognate receptors.
27. īļSignal threeī involves the polarization of CD4 T cells into either Th1, Th2, or regulatory T cells.
īļ Immature dendritic cells are polarized by the binding of type 1, type 2, or regulatory PAMP and differentiate into
mature dendritic cells that induce the formation of Th1, Th2, or T regulatory T cells, respectively.
īļ In general, viral-associated PAMP give rise to Th1 responses, and PAMP from parasitic organisms favour Th2
responses.
28. īļSignal fourī leads to spatial
imprinting of T cells, leading to
the acquisition of homing
receptors that induce selective
recirculation through the tissue in
which antigen was first
encountered.
īļ Dendritic cells from the intestine
uniquely produce retinoic acid,
inducing T cells to upregulate the
T cell gut-homing receptors a4b7
and CCR9 and suppress
expression of the skin-homing
receptor cutaneous lymphocyte
antigen (CLA).
īļ Signals that polarize T cells to
migrate to other sites, including
the skin, brain, and pulmonary
epithelia, have yet to be identified.
29. Natural Killer (NK) Cells
ī§ NK cells are large granular lymphocytes that constitutes 10-15% of peripheral blood
lymphocytes, derived from a separate lymphocyte linage.
ī§ They are cytotoxic but non-specific.
ī§ They are part of innate immunity and donât require prior contact with antigen.
ī§ NK cells act against the virus infected cells and tumor cells till the Tc cells are activated and
take over the function.
ī§ NK cells lack the T cell markers like CD3/4/8 (hence also called Null cells), instead they have CD
16& 56.
ī§ NK Cells donât differentiate into memory cells.
īļMechanism of NK cells mediated Cytotoxicity-
ī§ NK cells directly recognize certain ligands (Glycoproteins) present on the altered cell surface
without the help of MHC molecules.
ī§ This is mediated by 2 types of receptor present on NK cell surface (Theory of Opposing Signal
Model)
30. Natural Killer (NK) Cells
ī§ Activation receptors- (NKR-P1, CD 16): When these receptors are engaged with
ligands present on target cells, NK cells become activated.
ī§ Inhibitory Receptors- (C-type lectin inhibitory receptors)-
ī§ They recognize a part of MHC 1 molecules (HLA-E) which is present on all
nucleated cells.
ī§ Binding of inhibitory receptor to MHC 1 molecules generates an inhibitory signal
that suppresses NK cells even if they are bound to activation receptors.
ī§ However, in target cells, the MHC 1 expression is remarkably reduced. In
such cases there would not be any inhibitory signalī NK Cell activation.
īļ Target Cell destruction-
ī§ Mechanism of target cell lysis by NK cells and T cells are similar i.e. by secreting
Perforins and Granzymes. Perforins form pores on the target cell through
which granzymes enter and lyse the target cells.
32. Two ways to kill.
(A)Granule-mediated cytotoxicity is initiated by the targeted release of lytic
granules toward a locally attached target cell.
Granzymes can then enter the target cell by perforin-pores in the plasma
membrane (left) or by endocytosis and perforin-aided escape from endosomes
(right).
Granzymes can then induce caspase activation, mitochondrial dysfunction, or
caspase-independent apoptosis.
(B)Death receptor-mediated cytotoxicity is induced by surface expression of
FasL or TRAIL, which can engage and activate their respective receptor.
This results in caspase activation, mitochondrial dysfunction, and apoptosis.
33. Antibody dependent
cell mediated cytotoxicity (ADCC)-
ī§ A number of non-specific cytotoxic cells express receptors (FcR) on their
surface that can bind to Fc region of any immunoglobulin.
ī§ Following contact with a target cell coated with an antibody, these FcR
bearing cells can bind to Fc portion of the antibody coated on the target
cells, and subsequently cause lysis of the target cells.
ī§ Although these cells are non-specific for antigen, the specificity of the
antibody directs them towards the specific target cells. This type of
cytotoxicity is referred to as ADCC.
ī§ ADCC is shown by NK Cells, Macrophages, Neutrophils and
Eosinophils.
ī§ They release various cytotoxic factors into the target cells like perforins,
Granzymes, Lytic enzymes, free radicals, TNF etc.
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35.
36. Humoral/Antibody Mediated
Immune Response (HMI/AMI)
īļAMI occurs through the following 3 sequential stepsī
1. Activation of B-cells following contact with microbial antigen (B
cells act as APCs)
2. Proliferation and differentiation of B cells into effector cells
(antibody producing plasma cells) and Memory cells.
3. Effector Functionī Production of Abī . Neutralization
Opsonization
Complement
activation
37. A] HMI- Activation of B-cells
īļAntigens that activate B cells fall into 2 categoriesī
A. Most of the antigens are Thymus Dependent (TD):ī
īThey activate B cells indirectly via activation of T cells.
īActivated TH cellsī Cytokinesī Activation of B cells.
B. Thymus independent antigens (TI):ī
Antigens like bacterial capsule are not processed by APC and directly activate B cells without the
help of T cell cytokines.
īļActivation of B-cellsī
ī§ The first and foremost step that occurs is the recognition of TD antigen by B cell membrane
immunoglobulin (mIg) receptorī receptor mediated endocytosis of antigen.
ī§ Then the antigen is processed into smaller antigenic peptides that are presented in complex with
MHC-2 to activate TH cells (Endocytic pathway)
ī§ This leads to induction of 3 signalsī
38. A] HMI- Activation of B-cells
ī§ Signal-1:ī It is inducted by cross linkage of IgM on B cell membrane
with the microbial antigen.
ī§ Signal-2ī It is an additional signal provided by binding of CD 40 on
B cells with CD40L on activated TH cells.
ī§ Signal-3ī It is usually Cytokine stimulus due to TH cell produced
cytokines.
īļSignal Transductionī
ī§ Following induction of signal, its transmission is essential for B cell
activation and it is initiated by B Cell Receptor (BCR).
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43. B] HMI- Proliferation and
Differentiation of B-cells
ī§ Naïve B cells released from Bone Marrowī B cell areas of peripheral
lymphoid organs (Cortex of lymph node and marginal zone of
spleen.)ī Primary Lymphoid follicles.
ī§ Antigenic exposureī Activation of naïve B cellsī Proliferation.
ī§ Primary lymphoid folliclesī Secondary lymphoid folliclesī
Germinal Centers
Dark Zone
Light Zone
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47. B] HMI- Proliferation and
Differentiation of B-cells
īļEvents in the Dark Zone of Germinal Centerī
ī§ Activated B cellsī (differentiate)ī larger dividing cells â(Centroblasts)ī
transforms into nondividing cells, Centrocytes.
ī§ Centroblasts express membrane Ig by a process k/a Somatic Hypermutation.
ī§ This results in alteration of membrane Ig affinity by which it binds to
corresponding antigen.
ī§ Because somatic mutations occur randomly, they generate membrane Ig with
both High & Low affinity.
ī§ Centrocytes with low affinityī undergo Apoptosisī Phagocytosed by special
Tingible body Macrophages.
ī§ Centrocytes with high affinityī Survive and migrate to light zone.
ī§ The process of enhancement of Ig for Ag binding is called Affinity maturation.
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50. B] HMI- Proliferation and
Differentiation of B-cells
īļEvents in the light zone of Germinal Centerī
īąBinding of centrocytes to follicular dendritic cells->
ī§ The centrocytes with high affinity Ig undergo maturation by binding to a special type of
dendritic cells (Follicular Dendritic Cells- FDC).
ī§ Then the mature dendritic cells undergo class switch over.
īąClass Switch Over-
ī§ Early in the immune response IgM is the predominant immunoglobulin secreted by the B
cells.
ī§ But as the maturation progresses the same B cells undergo a phenomenon called CLASS
SWITCHING.
ī§ Binding of cytokines produced by TH cells induces Class Switch Over.
ī§ Different cytokines induce production of different classes of Ig by switching mechanism.
51. B] HMI- Proliferation and
Differentiation of B-cells
Cytokines Ig Class Produced
INF-đž IgG2a/ IgG3
IL-5 + TGF β IgA/ IgG2b
IL-4 IgE/G1/G4
IL-2,4,5 IgM
IL-4,5,6 +INF-đž IgG
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54. B] HMI- Proliferation and
Differentiation of B-cells
īąDifferentiation of centrocytes into Plasma cells and Memory Cellsī
ī§ After class switching , the selected centrocytes undergo further
differentiation into effector cells (Plasma cells) and Memory cells in
the light zone of germinal center.
ī§ Plasma cells are large Ab secreting cells; produce secretory Ig
enormously, but do not have membrane Ig or MHC class-2 molecules.
ī§ Memory B cells bear high affinity Ig of all classes as compared to
naïve B cells that only bear low affinity IgM/ IgD membrane Ig.
ī§ They are long lived cells which responds to secondary antigenic
stimulus.
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56. C] Effector Functions of AMI
ī§ Antibodies secreted from plasma cells perform a number of biological
functions.
ī§ Promotes Opsonization- FcRs, present on phagocytes surface recognize the
Ab coated microbesī Bindingī Enhanced phagocytosis.
ī§ Transcytosis- Movement of Ab via epithelial cells from their basolateral
side to apical side.
ī§ Mediates mucosal immunity- This is due to transcytosis of IgA mostly to
gut lumen that neutralizes microbes at local mucosal sites.
ī§ Activates complement mediated inflammation and cytolysis
ī§ Promotes ADCC.