Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis. There are two main types of Tregs: natural Tregs that develop in the thymus and express CD4 and CD25, and adaptive Tregs that acquire expression of CD25 in tissues outside the thymus during inflammation. Tregs exert their immunosuppressive effects through several mechanisms, including secreting cytokines like IL-10 and TGF-beta, expressing molecules like CTLA-4 that inhibit other immune cells, and inducing apoptosis in effector T cells. Adaptive Tregs mature in peripheral tissues under the influence of TGF-beta, where they gain expression of Treg markers and Foxp3, allowing them to se
This document outlines different types of regulatory T cells, including their identification, mechanisms of function, development processes, and properties. It discusses natural regulatory T cells that develop in the thymus and express high levels of CD25 and FoxP3, as well as induced regulatory T cells that develop in the periphery, including Tr1 cells that produce high levels of IL-10 and TGF-β, and Th3 cells that are induced following oral antigen administration and secrete TGF-β. The document also reviews CD8+ regulatory T cells and NKT regulatory cells, and compares the phenotypes, suppression mechanisms, targets, and roles of the different regulatory T cell subsets.
T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are developmentally distinct from Th1 and Th2 cells.
They create inflammation and tissue injury in autoimmune disease
1. Regulatory T cells (Tregs) that express the transcription factor Foxp3 play a key role in controlling immune responses and maintaining immunological self-tolerance. Depletion of Tregs can lead to development of autoimmune diseases and inflammatory conditions.
2. Foxp3 is required for the development and function of Tregs. Mutations that inactivate Foxp3 result in fatal autoimmune diseases in both mice and humans. Depletion of Tregs through the removal of CD25+ cells or neutralization of IL-2 can also induce autoimmunity in normal animals.
3. Tregs constitutively express high levels of CD25 (the IL-2 receptor alpha chain) and depend on IL
This study analyzed the gene expression profiles of two subsets of CD4+ T cells that express the ectoenzyme CD39: CD39+CD25+ T regulatory cells (Tregs) and CD39+CD25- T "inducer" cells (Tinds). Microarray analysis identified 96 genes differentially expressed between these subsets, including higher expression of KLRB1 (which encodes the CD161 protein) on Tinds. Flow cytometry confirmed higher CD161 protein levels on Tinds compared to Tregs. The findings suggest CD161 may be a marker for the novel Tind subset and provide insight into their immunoregulatory roles and functions.
Stat3 protein & t helper 17 cell -in psoriasis by yousry a mawlaM.YOUSRY Abdel-Mawla
This document discusses the roles of STAT3 and Th17 cells in psoriasis. STAT3 is activated by cytokines like IL-6 and transduces signals that lead to the transcription of genes involved in inflammation. Th17 cells secrete IL-17 which stimulates keratinocytes and drives the inflammatory response in psoriasis. The immune cells and cytokines involved create a vicious cycle that perpetuates the chronic inflammation and characteristic lesions of the disease.
This document discusses T helper 17 cells and their role in autoimmune diseases. It contains 3 figures: Figure 1 shows T cells and macrophages entering the central nervous system in a mouse model of multiple sclerosis, Figure 2 outlines the cytokines required for generating TH17 cells, and Figure 3 depicts the reciprocal expression of Foxp3 and IL-17 during T cell differentiation. The document also briefly mentions several autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and Crohn's disease, and potential molecular targeted therapies for these conditions including antibodies against TNF-α, IL-6, and possibly IL-17 in the future.
Stat3protein & immunocompetent cells in psoriasis pathogenesisM.YOUSRY Abdel-Mawla
STAT3 protein plays a role in the pathogenesis of psoriasis by activating immune cells. STAT3 is activated by cytokines and growth factors and acts as a signal transducer downstream of cytokine receptors. Activated STAT3 dimers enter the nucleus of immune cells and keratinocytes to induce genes that perpetuate inflammation in psoriasis. Overexpression of the Tie2 receptor in keratinocytes alone, not endothelial cells, is sufficient to induce a psoriasis-like phenotype in mouse models through increased dermal inflammation and keratinocyte proliferation.
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis. There are two main types of Tregs: natural Tregs that develop in the thymus and express CD4 and CD25, and adaptive Tregs that acquire expression of CD25 in tissues outside the thymus during inflammation. Tregs exert their immunosuppressive effects through several mechanisms, including secreting cytokines like IL-10 and TGF-beta, expressing molecules like CTLA-4 that inhibit other immune cells, and inducing apoptosis in effector T cells. Adaptive Tregs mature in peripheral tissues under the influence of TGF-beta, where they gain expression of Treg markers and Foxp3, allowing them to se
This document outlines different types of regulatory T cells, including their identification, mechanisms of function, development processes, and properties. It discusses natural regulatory T cells that develop in the thymus and express high levels of CD25 and FoxP3, as well as induced regulatory T cells that develop in the periphery, including Tr1 cells that produce high levels of IL-10 and TGF-β, and Th3 cells that are induced following oral antigen administration and secrete TGF-β. The document also reviews CD8+ regulatory T cells and NKT regulatory cells, and compares the phenotypes, suppression mechanisms, targets, and roles of the different regulatory T cell subsets.
T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are developmentally distinct from Th1 and Th2 cells.
They create inflammation and tissue injury in autoimmune disease
1. Regulatory T cells (Tregs) that express the transcription factor Foxp3 play a key role in controlling immune responses and maintaining immunological self-tolerance. Depletion of Tregs can lead to development of autoimmune diseases and inflammatory conditions.
2. Foxp3 is required for the development and function of Tregs. Mutations that inactivate Foxp3 result in fatal autoimmune diseases in both mice and humans. Depletion of Tregs through the removal of CD25+ cells or neutralization of IL-2 can also induce autoimmunity in normal animals.
3. Tregs constitutively express high levels of CD25 (the IL-2 receptor alpha chain) and depend on IL
This study analyzed the gene expression profiles of two subsets of CD4+ T cells that express the ectoenzyme CD39: CD39+CD25+ T regulatory cells (Tregs) and CD39+CD25- T "inducer" cells (Tinds). Microarray analysis identified 96 genes differentially expressed between these subsets, including higher expression of KLRB1 (which encodes the CD161 protein) on Tinds. Flow cytometry confirmed higher CD161 protein levels on Tinds compared to Tregs. The findings suggest CD161 may be a marker for the novel Tind subset and provide insight into their immunoregulatory roles and functions.
Stat3 protein & t helper 17 cell -in psoriasis by yousry a mawlaM.YOUSRY Abdel-Mawla
This document discusses the roles of STAT3 and Th17 cells in psoriasis. STAT3 is activated by cytokines like IL-6 and transduces signals that lead to the transcription of genes involved in inflammation. Th17 cells secrete IL-17 which stimulates keratinocytes and drives the inflammatory response in psoriasis. The immune cells and cytokines involved create a vicious cycle that perpetuates the chronic inflammation and characteristic lesions of the disease.
This document discusses T helper 17 cells and their role in autoimmune diseases. It contains 3 figures: Figure 1 shows T cells and macrophages entering the central nervous system in a mouse model of multiple sclerosis, Figure 2 outlines the cytokines required for generating TH17 cells, and Figure 3 depicts the reciprocal expression of Foxp3 and IL-17 during T cell differentiation. The document also briefly mentions several autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and Crohn's disease, and potential molecular targeted therapies for these conditions including antibodies against TNF-α, IL-6, and possibly IL-17 in the future.
Stat3protein & immunocompetent cells in psoriasis pathogenesisM.YOUSRY Abdel-Mawla
STAT3 protein plays a role in the pathogenesis of psoriasis by activating immune cells. STAT3 is activated by cytokines and growth factors and acts as a signal transducer downstream of cytokine receptors. Activated STAT3 dimers enter the nucleus of immune cells and keratinocytes to induce genes that perpetuate inflammation in psoriasis. Overexpression of the Tie2 receptor in keratinocytes alone, not endothelial cells, is sufficient to induce a psoriasis-like phenotype in mouse models through increased dermal inflammation and keratinocyte proliferation.
Stat3 protein & immunocompetent cells cross talks in psoriasis by yousr...M.YOUSRY Abdel-Mawla
The document discusses the role of STAT3 protein and immune cells in psoriasis. STAT3 is activated by cytokines and growth factors and acts as a signal transducer downstream of cytokine receptors. It plays a key role in dendritic cell development. In psoriasis, plasmacytoid dendritic cells produce interferon-α which activates T cells and drives the development of psoriatic lesions through a positive feedback loop between immune cells and keratinocytes.
Helper T cells help other immune cells by releasing cytokines. They differentiate into two main subtypes, TH1 and TH2 cells, which are defined by the distinct cytokines they produce. TH1 cells secrete cytokines like IFN-gamma and TNF-beta that stimulate immune responses against intracellular pathogens. TH2 cells secrete cytokines like IL-4, IL-5, and IL-13 that help B cells produce antibodies and stimulate responses against extracellular parasites. The specific cytokines TH1 and TH2 cells are exposed to during activation determine whether they differentiate into those subtypes.
Stat3 protein & immunocompetent cells cross talks in psoriasis by yousr...M.YOUSRY Abdel-Mawla
STAT 3 protein plays a role in cross-talk between immune cells and keratinocytes in psoriasis. STAT3 is activated by cytokines and growth factors and activates transcription of target genes. In psoriasis, dendritic cells and T cells are activated, forming an immunological synapse that triggers keratinocyte proliferation, altered differentiation, and angiogenesis through cytokine and chemokine release. Plasmacytoid dendritic cells accumulate in pre-psoriatic skin and secrete interferon-α early in disease formation, triggering autoimmune inflammation and psoriasis development.
Antigen specific T cell activation assay is one of the technologies we can provide during the one-stop service which can activate CAR-T cells for further downstream research or clinical trials. T cell activation requires at least two signals to be fully activated. The first signal is provided by the interaction of T cell antigen-specific receptor and the antigen-major histocompatibility complex (MHC).
https://www.creative-biolabs.com/car-t/antigen-specific-t-cell-activation-assay.htm
1) The study investigated the role of the LAT-PLCγ1 interaction in γδ T cell development and homeostasis by crossing LATY136F mice, which lack this interaction, with TCRβ−/− mice.
2) Results showed the LATY136F mutation partially blocked γδ T cell development in the thymus. However, epithelial γδ T cells were still present in the skin and intestine.
3) Interestingly, a population of CD4+ γδ T cells in the spleen and lymph nodes of LATY136F/TCRβ−/− mice underwent rapid proliferation, producing elevated IL-4 and causing autoimmunity. This suggested LAT signaling functions differently in distinct
Regulatory T cells (Tregs) suppress anti-tumor immune responses, allowing cancers to evade detection. Tregs are overrepresented in cancers like melanoma, helping the tumor establish an immunosuppressive microenvironment. Blocking Treg activity through antibodies against CTLA-4 prevents Treg proliferation while pushing other T cells towards an anti-tumor Th17 profile, limiting Treg differentiation and freeing up interleukin-2 (IL-2) for cytotoxic T cell expansion. Combining CTLA-4 blockade with IL-2 therapy could activate cytotoxic CD8+ T cells to destroy tumors by inducing granzyme and perforin expression for lysis of cancer cells.
This document discusses the role of STAT3 and Th17 cells in psoriasis. STAT3 is activated by cytokines and plays a key role in Th17 cell differentiation. Th17 cells secrete IL-17 and IL-22, driving keratinocyte hyperproliferation in psoriasis. Blocking STAT3 inhibits the development and progression of psoriatic lesions, suggesting STAT3 is a potential therapeutic target for treating psoriasis.
STAT 3 and Other Target Proteins: New Concepts in Psoriasis Pathogenesis & Therapy
This document discusses STAT3 signaling and its role in psoriasis pathogenesis. It summarizes that:
1) STAT3 is activated by cytokines and growth factors and forms dimers that enter the nucleus and activate gene transcription.
2) STAT3 signaling is involved in processes like proliferation and differentiation of keratinocytes. Its dysregulation contributes to psoriasis pathogenesis.
3) Psoriasis is a chronic inflammatory skin disease involving excessive keratinocyte proliferation, abnormal differentiation, and immune system involvement. Understanding STAT3 signaling may provide novel therapeutic targets for psoriasis treatment.
This document discusses the role of dendritic cells (DCs) in autoimmune diseases. It begins by introducing DCs as professional antigen presenting cells that are involved in both inducing immune responses and maintaining peripheral tolerance. The review then examines the different DC subsets and their potential roles in tolerance induction. It discusses factors that influence the generation of tolerogenic DCs, including their maturation status, intrinsic characteristics, interactions with other immune cells, and the tissue microenvironment. The review challenges the traditional view that immature DCs induce tolerance, presenting evidence that both immature and mature DCs can induce tolerance depending on other factors. It highlights the need to better define the features of DC subsets that induce tolerance.
Role of stat3 protein & thelper 17 cell in psoriasis development by yousryM.YOUSRY Abdel-Mawla
This document discusses the role of STAT3 and Th17 cells in the development of psoriasis. It describes how STAT3 signaling regulates the differentiation of naive T cells into Th17 cells through the production of cytokines like IL-6, IL-21, and IL-23. Th17 cells secrete pro-inflammatory cytokines like IL-17 and IL-22 that contribute to psoriasis by stimulating keratinocyte growth and activation. The overexpression of Th17 cells and cytokines in the skin is thought to play a key role in the pathogenesis of psoriasis.
This document summarizes the role of STAT3 and Th17 cells in the immunopathogenesis of psoriasis. STAT3 is activated by cytokines like IL-6 and IL-23, driving the differentiation of Th17 cells which secrete IL-17 and IL-22. IL-17 and IL-22 stimulate keratinocyte proliferation, a hallmark of psoriatic plaques. Blocking STAT3 inhibits the development and progression of psoriatic lesions in animal models. Th17 cells and the STAT3 pathway are now considered key therapeutic targets for psoriasis treatment.
TGF-β and IL-1 are cytokines that regulate immune responses. TGF-β regulates T cell development, homeostasis, and differentiation. It promotes regulatory T cells and inhibits effector T cell differentiation. IL-1 is produced by monocytes and macrophages in response to infection. It stimulates T cell and B cell proliferation and the inflammatory response. Both cytokines signal through cell surface receptors to modulate immune function.
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
Enhanicing cd8 tcell memory by modulating fatty acid metabolismeman youssif
1) Mice with a T cell-specific deletion of TRAF6 mounted normal CD8+ T cell effector responses but had a profound defect in their ability to generate long-lived memory CD8+ T cells.
2) Microarray analysis revealed that TRAF6-deficient CD8+ T cells had altered expression of genes involved in fatty acid metabolism.
3) Administration of the anti-diabetic drug metformin, which promotes fatty acid metabolism, restored fatty acid oxidation in TRAF6-deficient CD8+ T cells and improved their ability to generate memory cells. Metformin treatment also increased the efficacy of an experimental anti-cancer vaccine by boosting memory CD8+ T cell responses.
This document summarizes two scientific articles about Programmed Death-1 (PD-1) and its ligands PD-L1 and PD-L2. The first article analyzes the basal and induced expression of PD-1 ligands in three chordoma cell lines and finds that while basal expression is low, expression is upregulated by IFN-γ but not IL-4. The second article examines blocking the PD-1/PD-L1 pathway to prevent loss of effector function in adoptively transferred central memory CD8+ T cells against tumors.
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.
This document discusses using ex vivo expanded and fucosylated regulatory T cells (Tregs) from third party umbilical cord blood to prevent graft-versus-host disease (GVHD) after transplantation. Experiments in mice show that fucosylated Tregs home more effectively to sites of inflammation, persist longer in vivo, and reduce GVHD symptoms and mortality more than untreated Tregs. The document proposes a clinical trial to evaluate the safety and efficacy of fucosylated Tregs for preventing GVHD in patients receiving double cord blood transplants.
Continuous engagement of self specific activation receptor induces nk toleranceEhdaa Smadi
This study investigated the effects of persistent engagement of the activating NK cell receptor Ly49H with its ligand m157. The results showed that transgenic expression of m157 in mice led to downregulation of Ly49H receptor expression on NK cells and impaired Ly49H+ NK cell function. Specifically, Ly49H+ NK cells from m157 transgenic mice produced less IFN-γ upon stimulation. However, adoptive transfer experiments demonstrated the defect in Ly49H+ NK cells was reversible and did not depend on the level of Ly49H expression. Continuous engagement of Ly49H with m157 was necessary to induce Ly49H dysfunction, providing evidence that persistent receptor stimulation can impair NK cell responses.
The document discusses interleukin-17 (IL-17) and its role in psoriasis. It describes how IL-17 is produced by T-helper 17 cells and promotes neutrophil recruitment and defense against extracellular pathogens. Blocking IL-17 has shown efficacy in clinical trials for the treatment of psoriasis. The document also reviews the IL-17 family of cytokines and their functions, receptors, and role in immune responses.
Regulatory T-cells (Tregs) help maintain self-tolerance and prevent autoimmunity by suppressing immune responses. They express FOXP3 and CD25 and function through various mechanisms like secreting inhibitory cytokines or metabolizing IL-2. Tregs are implicated in tumor immune escape by suppressing anti-tumor immunity. While Tregs are normally beneficial, in cancer high levels associate with poor prognosis by hindering immune response. Emerging immunotherapies aim to deplete or modulate Tregs to enhance anti-tumor immunity.
Toll-like receptors (TLRs) are expressed by both immune cells like dendritic cells and T cells. While TLRs were traditionally thought to only regulate innate immunity, the document discusses recent evidence that TLRs expressed on T cells can directly modulate adaptive immune responses. TLRs on T cells may function as co-stimulatory molecules that enhance T cell proliferation, survival and cytokine production when activated along with the T cell receptor. The direct involvement of TLRs in T cell immunity suggests they could play a role in autoimmune diseases, infections and graft rejection.
Stat3 protein & immunocompetent cells cross talks in psoriasis by yousr...M.YOUSRY Abdel-Mawla
The document discusses the role of STAT3 protein and immune cells in psoriasis. STAT3 is activated by cytokines and growth factors and acts as a signal transducer downstream of cytokine receptors. It plays a key role in dendritic cell development. In psoriasis, plasmacytoid dendritic cells produce interferon-α which activates T cells and drives the development of psoriatic lesions through a positive feedback loop between immune cells and keratinocytes.
Helper T cells help other immune cells by releasing cytokines. They differentiate into two main subtypes, TH1 and TH2 cells, which are defined by the distinct cytokines they produce. TH1 cells secrete cytokines like IFN-gamma and TNF-beta that stimulate immune responses against intracellular pathogens. TH2 cells secrete cytokines like IL-4, IL-5, and IL-13 that help B cells produce antibodies and stimulate responses against extracellular parasites. The specific cytokines TH1 and TH2 cells are exposed to during activation determine whether they differentiate into those subtypes.
Stat3 protein & immunocompetent cells cross talks in psoriasis by yousr...M.YOUSRY Abdel-Mawla
STAT 3 protein plays a role in cross-talk between immune cells and keratinocytes in psoriasis. STAT3 is activated by cytokines and growth factors and activates transcription of target genes. In psoriasis, dendritic cells and T cells are activated, forming an immunological synapse that triggers keratinocyte proliferation, altered differentiation, and angiogenesis through cytokine and chemokine release. Plasmacytoid dendritic cells accumulate in pre-psoriatic skin and secrete interferon-α early in disease formation, triggering autoimmune inflammation and psoriasis development.
Antigen specific T cell activation assay is one of the technologies we can provide during the one-stop service which can activate CAR-T cells for further downstream research or clinical trials. T cell activation requires at least two signals to be fully activated. The first signal is provided by the interaction of T cell antigen-specific receptor and the antigen-major histocompatibility complex (MHC).
https://www.creative-biolabs.com/car-t/antigen-specific-t-cell-activation-assay.htm
1) The study investigated the role of the LAT-PLCγ1 interaction in γδ T cell development and homeostasis by crossing LATY136F mice, which lack this interaction, with TCRβ−/− mice.
2) Results showed the LATY136F mutation partially blocked γδ T cell development in the thymus. However, epithelial γδ T cells were still present in the skin and intestine.
3) Interestingly, a population of CD4+ γδ T cells in the spleen and lymph nodes of LATY136F/TCRβ−/− mice underwent rapid proliferation, producing elevated IL-4 and causing autoimmunity. This suggested LAT signaling functions differently in distinct
Regulatory T cells (Tregs) suppress anti-tumor immune responses, allowing cancers to evade detection. Tregs are overrepresented in cancers like melanoma, helping the tumor establish an immunosuppressive microenvironment. Blocking Treg activity through antibodies against CTLA-4 prevents Treg proliferation while pushing other T cells towards an anti-tumor Th17 profile, limiting Treg differentiation and freeing up interleukin-2 (IL-2) for cytotoxic T cell expansion. Combining CTLA-4 blockade with IL-2 therapy could activate cytotoxic CD8+ T cells to destroy tumors by inducing granzyme and perforin expression for lysis of cancer cells.
This document discusses the role of STAT3 and Th17 cells in psoriasis. STAT3 is activated by cytokines and plays a key role in Th17 cell differentiation. Th17 cells secrete IL-17 and IL-22, driving keratinocyte hyperproliferation in psoriasis. Blocking STAT3 inhibits the development and progression of psoriatic lesions, suggesting STAT3 is a potential therapeutic target for treating psoriasis.
STAT 3 and Other Target Proteins: New Concepts in Psoriasis Pathogenesis & Therapy
This document discusses STAT3 signaling and its role in psoriasis pathogenesis. It summarizes that:
1) STAT3 is activated by cytokines and growth factors and forms dimers that enter the nucleus and activate gene transcription.
2) STAT3 signaling is involved in processes like proliferation and differentiation of keratinocytes. Its dysregulation contributes to psoriasis pathogenesis.
3) Psoriasis is a chronic inflammatory skin disease involving excessive keratinocyte proliferation, abnormal differentiation, and immune system involvement. Understanding STAT3 signaling may provide novel therapeutic targets for psoriasis treatment.
This document discusses the role of dendritic cells (DCs) in autoimmune diseases. It begins by introducing DCs as professional antigen presenting cells that are involved in both inducing immune responses and maintaining peripheral tolerance. The review then examines the different DC subsets and their potential roles in tolerance induction. It discusses factors that influence the generation of tolerogenic DCs, including their maturation status, intrinsic characteristics, interactions with other immune cells, and the tissue microenvironment. The review challenges the traditional view that immature DCs induce tolerance, presenting evidence that both immature and mature DCs can induce tolerance depending on other factors. It highlights the need to better define the features of DC subsets that induce tolerance.
Role of stat3 protein & thelper 17 cell in psoriasis development by yousryM.YOUSRY Abdel-Mawla
This document discusses the role of STAT3 and Th17 cells in the development of psoriasis. It describes how STAT3 signaling regulates the differentiation of naive T cells into Th17 cells through the production of cytokines like IL-6, IL-21, and IL-23. Th17 cells secrete pro-inflammatory cytokines like IL-17 and IL-22 that contribute to psoriasis by stimulating keratinocyte growth and activation. The overexpression of Th17 cells and cytokines in the skin is thought to play a key role in the pathogenesis of psoriasis.
This document summarizes the role of STAT3 and Th17 cells in the immunopathogenesis of psoriasis. STAT3 is activated by cytokines like IL-6 and IL-23, driving the differentiation of Th17 cells which secrete IL-17 and IL-22. IL-17 and IL-22 stimulate keratinocyte proliferation, a hallmark of psoriatic plaques. Blocking STAT3 inhibits the development and progression of psoriatic lesions in animal models. Th17 cells and the STAT3 pathway are now considered key therapeutic targets for psoriasis treatment.
TGF-β and IL-1 are cytokines that regulate immune responses. TGF-β regulates T cell development, homeostasis, and differentiation. It promotes regulatory T cells and inhibits effector T cell differentiation. IL-1 is produced by monocytes and macrophages in response to infection. It stimulates T cell and B cell proliferation and the inflammatory response. Both cytokines signal through cell surface receptors to modulate immune function.
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
Enhanicing cd8 tcell memory by modulating fatty acid metabolismeman youssif
1) Mice with a T cell-specific deletion of TRAF6 mounted normal CD8+ T cell effector responses but had a profound defect in their ability to generate long-lived memory CD8+ T cells.
2) Microarray analysis revealed that TRAF6-deficient CD8+ T cells had altered expression of genes involved in fatty acid metabolism.
3) Administration of the anti-diabetic drug metformin, which promotes fatty acid metabolism, restored fatty acid oxidation in TRAF6-deficient CD8+ T cells and improved their ability to generate memory cells. Metformin treatment also increased the efficacy of an experimental anti-cancer vaccine by boosting memory CD8+ T cell responses.
This document summarizes two scientific articles about Programmed Death-1 (PD-1) and its ligands PD-L1 and PD-L2. The first article analyzes the basal and induced expression of PD-1 ligands in three chordoma cell lines and finds that while basal expression is low, expression is upregulated by IFN-γ but not IL-4. The second article examines blocking the PD-1/PD-L1 pathway to prevent loss of effector function in adoptively transferred central memory CD8+ T cells against tumors.
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.
This document discusses using ex vivo expanded and fucosylated regulatory T cells (Tregs) from third party umbilical cord blood to prevent graft-versus-host disease (GVHD) after transplantation. Experiments in mice show that fucosylated Tregs home more effectively to sites of inflammation, persist longer in vivo, and reduce GVHD symptoms and mortality more than untreated Tregs. The document proposes a clinical trial to evaluate the safety and efficacy of fucosylated Tregs for preventing GVHD in patients receiving double cord blood transplants.
Continuous engagement of self specific activation receptor induces nk toleranceEhdaa Smadi
This study investigated the effects of persistent engagement of the activating NK cell receptor Ly49H with its ligand m157. The results showed that transgenic expression of m157 in mice led to downregulation of Ly49H receptor expression on NK cells and impaired Ly49H+ NK cell function. Specifically, Ly49H+ NK cells from m157 transgenic mice produced less IFN-γ upon stimulation. However, adoptive transfer experiments demonstrated the defect in Ly49H+ NK cells was reversible and did not depend on the level of Ly49H expression. Continuous engagement of Ly49H with m157 was necessary to induce Ly49H dysfunction, providing evidence that persistent receptor stimulation can impair NK cell responses.
The document discusses interleukin-17 (IL-17) and its role in psoriasis. It describes how IL-17 is produced by T-helper 17 cells and promotes neutrophil recruitment and defense against extracellular pathogens. Blocking IL-17 has shown efficacy in clinical trials for the treatment of psoriasis. The document also reviews the IL-17 family of cytokines and their functions, receptors, and role in immune responses.
Regulatory T-cells (Tregs) help maintain self-tolerance and prevent autoimmunity by suppressing immune responses. They express FOXP3 and CD25 and function through various mechanisms like secreting inhibitory cytokines or metabolizing IL-2. Tregs are implicated in tumor immune escape by suppressing anti-tumor immunity. While Tregs are normally beneficial, in cancer high levels associate with poor prognosis by hindering immune response. Emerging immunotherapies aim to deplete or modulate Tregs to enhance anti-tumor immunity.
Toll-like receptors (TLRs) are expressed by both immune cells like dendritic cells and T cells. While TLRs were traditionally thought to only regulate innate immunity, the document discusses recent evidence that TLRs expressed on T cells can directly modulate adaptive immune responses. TLRs on T cells may function as co-stimulatory molecules that enhance T cell proliferation, survival and cytokine production when activated along with the T cell receptor. The direct involvement of TLRs in T cell immunity suggests they could play a role in autoimmune diseases, infections and graft rejection.
This document summarizes the key stages in T-cell maturation, activation, and differentiation. It discusses how T-cells mature in the thymus through positive and negative selection to screen for self-MHC restriction and eliminate self-reactive cells. Activation requires signal 1 through TCR-antigen-MHC interaction and signal 2 via co-stimulatory molecules. Upon activation, T-cells can proliferate and differentiate into memory cells or effector cells. CD4 and CD8 T-cells leave the thymus as naive cells and, upon antigen recognition, can become activated and further differentiate.
The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" ma...Retired from EASTMAN KODAK
The document discusses how the enzyme IDO may be the missing link in T-cell activation in response to vaccines and immunotherapy. IDO produced by tumors inhibits the production of interleukin-6 (IL-6), which is important for the differentiation of T-cells into effector T-cells like TH17 cells. Without IL-6, T-cells instead differentiate into regulatory T-cells, weakening the immune response. The document hypothesizes that combining an IDO inhibitor with immunotherapies like anti-CTLA4 antibodies could help boost immune responses in cancer patients.
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and suppressing excessive immune responses. Tregs can develop naturally in the thymus or be induced in the periphery. They express the transcription factor FoxP3 and surface markers CD4 and CD25. Tregs suppress the activation and functions of other immune cells and help prevent autoimmunity, control infections, allow transplantation tolerance, and support fetal-maternal tolerance in pregnancy. Dysregulation of Tregs has been linked to immunological diseases. Therapeutic use of Tregs may help treat diseases driven by excessive immune responses like autoimmunity.
T cells can be categorized into several subsets including helper T cells, cytotoxic T cells, memory T cells, and regulatory T cells. Helper T cells assist other immune cells, cytotoxic T cells destroy infected and tumor cells, memory T cells provide faster responses upon reexposure to pathogens, and regulatory T cells suppress immune activation and prevent autoimmunity. Understanding regulatory T cells in HIV-1 could lead to new immunotherapy or vaccine strategies, but their exact role in HIV-1 pathogenesis requires further study.
This document discusses regulatory T cells (Tregs) as potential therapeutic targets for rheumatoid arthritis (RA). It begins with an introduction to RA, describing its causes, symptoms, risk factors, and current diagnostic tools and drug treatments. It then discusses Tregs, which suppress immune responses and help maintain tolerance. Several drugs are proposed that could promote Treg function or numbers to restore normal immune regulation in RA, including TNF inhibitors, T cell costimulatory blocking agents, TLR antagonists, HDAC inhibitors, and interleukin-2. The document concludes that controlling regulatory immune mechanisms through targeting Tregs may provide novel therapeutic approaches for treating autoimmune diseases like RA.
T CELL ACTIVATION AND IT'S TERMINATIONpremvarma064
T cell activation requires two signals: 1) recognition of antigens displayed on antigen-presenting cells by T cell receptors and 2) co-stimulatory signals through molecules like CD28. This leads T cells to proliferate, differentiate into effector and memory cells, and perform effector functions. Proper activation requires interaction between T cells and antigen-presenting cells in lymphoid tissues, where costimulatory molecules are highly expressed. Dysregulation of T cell activation can lead to autoimmunity or susceptibility to infection.
This document provides an overview of T cell interaction and function. It discusses the major components of the immune system including lymphoid organs and lymphocytes. It describes the different types of T cells including T helper cells, cytotoxic T cells, regulatory T cells, and memory T cells. It explains T cell receptors, the MHC complex, and CD markers. It also covers T cell differentiation, activation, and effector functions. Finally, it briefly discusses tolerance and how self-reactive T cells can lead to autoimmune diseases when tolerance is broken.
T-lymphocytes can only be activated by antigen complexes with HLA antigens from the person the lymphocytes originated from. During development in the thymus, lymphocytes that react with self-antigens presented by HLA die while those that recognize foreign antigens with a low affinity survive in a process called positive selection. Negatively selecting eliminates lymphocytes that react strongly to self-antigens. This results in a T-cell population that can recognize foreign peptides bound to self-HLA molecules.
1. The document discusses mechanisms of central and peripheral tolerance that prevent autoimmune diseases. Central tolerance involves positive and negative selection in the thymus to eliminate self-reactive T cells, aided by the AIRE gene.
2. Peripheral tolerance mechanisms help control self-reactive T cells that escape thymic selection. These include clonal deletion, anergy, and regulation by Treg cells. Anergy involves a lack of response upon re-exposure to self-antigen.
3. Tolerance is important physiologically for organ transplants, maternal-fetal tolerance, and tolerance of commensal gut microbes. A breakdown in tolerance can lead to autoimmune diseases.
This document discusses breaking immune tolerance to cancer (melanoma) by targeting regulatory T cells (Tregs). It suggests that Tregs suppress anti-tumor immune responses by secreting cytokines like TGF-β and IL-10. Depleting Tregs using cyclophosphamide or blocking CTLA-4 with ipilimumab can help activate the immune system. However, some tumors lack "danger signals" like inflammatory cytokines needed to recruit T cells. Stimulating toll-like receptor 4 on macrophages may induce cytokines like IL-6, IL-1β, and TNFα that create an inflammatory microenvironment and promote anti-tumor immunity.
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.
This document summarizes cell-mediated immune responses by T lymphocytes. It discusses:
1) The phases of T cell responses including antigen recognition, costimulation, differentiation into effector cells, and signal attenuation.
2) How T cells recognize antigens through the T cell receptor complex and costimulatory molecules help activate T cells.
3) The roles and mechanisms of effector T cell subsets like Th1, Th2, and cytotoxic CD8+ T cells in fighting infection through secretion of cytokines and direct killing of infected cells.
4) How effector T cells migrate and are retained at sites of infection through adhesion molecules and homing receptors.
This document summarizes T cells and their activation process. It describes how T cells develop from stem cells in the bone marrow then migrate to the thymus to mature. The main types of mature T cells are helper CD4+ T cells and cytotoxic CD8+ T cells. Activation of T cells requires two signals: recognition of antigen by the T cell receptor, and a costimulatory signal such as CD28 binding. When activated, T cells proliferate and secrete cytokines like IL-2 that stimulate immune responses. Memory T cells provide long-lasting immunity upon pathogen reexposure.
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
1) The document discusses models of how regulatory T cells (Tregs) develop in the thymus from precursor cells.
2) Early evidence suggested Treg development depends on the specificity and affinity of the T cell receptor (TCR) for self-antigens, but more recent data challenged this idea.
3) New evidence supports TCR specificity playing an important role, finding that certain TCRs efficiently drive Treg differentiation when expressed at low clonal frequencies, but not at high frequencies due to competition for a limited niche.
This document summarizes various inflammatory mediators including cytokines, chemokines, lipid mediators, and neuropeptides. It describes the sources and functions of different cytokines such as IL-1, TNF-α, IFN-γ, and chemokines such as IL-8 and RANTES. It also discusses the roles of lipid mediators like leukotrienes and prostaglandins in inflammation.
This document provides an overview of mucosal-associated invariant T cells (MAIT). It discusses that MAIT cells are a type of innate alpha beta T cell that express a semi-invariant T cell receptor and recognize bacterial vitamin B metabolites presented by MR1. The document outlines that MAIT cells make up a significant percentage of T cells in the human body, particularly in the mucosa and liver. Their functions include roles in early detection of bacterial infection through cytokine production and cytotoxic activity. The document also notes that MAIT cells have been found infiltrating various human tumor tissues.
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A review on prevention of graft-versus-host disease by the donor T regulatory cells with conventional T cells
1. konakalla manikanta et al., / Journal of Pharmacreations Vol-2(1) 2015 [1-9]
1
Pharmacreations | Volume 2 | Issue 1 | Jan-Mar-2015
Journal Home page: www.pharmacreations.com
Review article Open Access
A review on prevention of graft-versus-host disease by the donor T
regulatory cells with conventional T cells
Konakalla Manikanta*, Limna.A.L, Konakalla Madhurisudha, Bhama.S, Sambath
Kumar.R
Department of pharmacy practice, J.K.K. Nattraja College of Pharmacy, Komarapalayam-
638183, Namakkal (Dt), Tamilnadu.
*Corresponding author: Konakalla manikanta
E-mail id: manikanta.k099@gmail.com
ABSTRACT
Graft-versus host disease is the major risk after stem cell transplantation. Stem cells of the donor, after
transplantation attacks the immune system of the recipient’s body and causes graft-versus host disease. Regulatory T
cells represent a novel cell based approach for potentially reducing the risk of graft versus host disease (GVHD).
Regulatory T cells (Tregs) are a subpopulation of CD4+
T cells by the suppressive action on immune responses.
These cells are also responsible for limiting tissue damage during ongoing and resolving immune responses. Before
haemopoeitic stem cell transplantation, infusion of donor T regulatory cells with conventional T cells prevent graft
versus host disease and promotes immune system recovery. After infusion of activated donor regulatory T cells the
release of interleukin-10 and repress the activation of conventional T cells and thereby blocks rejection. Regulatory
T cells and conventional T cells control adaptive immunity against pathogens and cancer by activating other effector
immune cells.
Keywords: Regulatory T cells; Graft versus host disease; Haemopoeitic stem cell transplantation; Antigen
presenting cells; Mixed lymphocyte reaction.
INTRODUCTION
Regulatory T cells maintain tolerance against
antigens of its own and suppress autoimmune
diseases. Mouse models suggest that modulation of
Tregs can treat autoimmune disease and cancer and
facilitate organ transplantation. Regulatory T cells of
natural or induced type suppress T cells, especially
naturally arising CD25+
and CD4+
Tregs, in which
expression of the transcription factor forkhead box p3
(Foxp3) occurs in the thymusgical immune responses.
Regulatory T cells suppress the activation of the
immune system and prevent autoimmune diseases.
The role of regulatory T cells play within the immune
system is evidenced by the severe autoimmune
diseases that results from a genetic deficiency in
regulatory T cells. T regulatory cells were classified
into two types, they are natural (derived in the
thymus) or induced (derived in the periphery).
Thymus-derived regulatory T cells are homogeneous
in population until they migrate into periphery from
thymus gland, where a subpopulation of these cells
can develop similar to conventional cells, memory
cells and effector T cells. This change of regulatory T
cells enables their migration to lymphoid and non-
lymphoid tissues to maintain immune homeostasis. In
Journal of Pharmacreations
2. konakalla manikanta et al., / Journal of Pharmacreations Vol-2(1) 2015 [1-9]
2
the periphery, T regulatory cells develop from
conventional T cells.
Depending on the experimental model system
studied, all induced Tregs not express Foxp3+
or
CD25+
. Reports also demonstrate that, unlike
thymically-derived Tregs, induced Tregs do not
express high levels of Foxp3+
and CD25+
. Contrary to
conventional T cells, T regulatory cells express both
glycoprotein A repetitions predominant (GARP), a
membrane protein and tissue growth factor-beta
transiently on their surface upon T cell receptor
activation. Additional T regulatory cells subsets can
be defined based on the expression of chemokine
receptors and adhesion molecules.
Suppressive mechanisms of regulatory T cell
Secretion of IL-10
The secretion of Interleukin (IL)-10 serves
directly or indirectly to inhibit effector T cell
responses. Treg cells also secret IL-35 and TGF-
β to induce conventional CD4+
T cells to
differentiate into Treg cells, thereby skewing the
ratio of Tregs to T helper cells during an immune
response.
CTLA-4 and cell surface molecules
Equally as important as IL-10 secretion, cell
surface molecules such as cytotoxic T
lymphocyte antigen 4 (CTLA-4) also participate
in Treg cell-mediated suppression.
Cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) inhibits dendritic cell (DC) mediated
T cell stimulation by binding to CD80 and
CD86, which leads to down regulation of these
co-stimulatory molecules on the DC and
induction of indoleamine 2,3-dioxygenase (IDO),
an enzyme that depletes tryptophan from the
microenvironment.
Master regulators
Tregs use master regulators typically associated
with specific T helper subsets also regulate the
immune response customarily performed by
those subsets.
Thus, understanding the mechanisms by which Tregs
exert their suppressive function has broad
implications for drug development strategies aimed at
treating cancer, diabetes and other autoimmune
diseases.
Cell type phenotype Suggested immunosuppressive
mechanism
CD4+
Natural
regulatory T
cells(nTreg)
CD25+
Foxp3+
45RO+
CTLA-
4+
GITR+
CD134+
CD62L+
CD103+
lymphocyte activation
gene-3+
CD12710CD26+
Cell-to-Cell contact-depend in vitro
(CTLA-4) Cell-to-Cell contact,
cytokine-mediated(IL-10>>TGF-β,IL-
5,IFN Production)
Cytokine-mediated(IL-10 and TGF-β
Production)
Inducible
regulatory T
cells (iTreg)
Th3
Tr1
CD25+
Foxp3+
45RO+
CTLA-4+
CD25+
Foxp3+
45RO+
CTLA-4-
Cytokine-mediated(TGF-β
Production>>IL-10)
Cell-to-Cell contact, Cytokine-mediated
( IL-10>>TGF-β,IL-5,IFN production)
TGF-β/IL-10
Double positive
Treg
CD25-Foxp3 cells Cytokine-mediated(IL-10 and TGF-β
Production)
CD8+
T suppressor
cells
Naturally
occuring
Fox p3+
45RO+
CD25+
CTLA-4+
GITR+
Cell-to-Cell contact-depend(CTLA-4)
Cytokine-mediated( TGF-β Production)
Cytokine-mediated( IL-10
production)
Non-antigen
specific
inducible
CD28+
Foxp3+
CD56+
CD25+
Foxp3+
CD28+
GIRT+
CTLA-4
Cell-to-Cell contact
Cell-to-Cell contact, Cytokine-
mediated(IL-2,IL-10,IL-7,IFN-,TGF-β
production)
3. konakalla manikanta et al., / Journal of Pharmacreations Vol-2(1) 2015 [1-9]
3
PHENOTYPE OR MARKER MOLECULES
OF TREGS
Tregs were originally defined on the basis of
constitutive expression of surface CD4 antigen and
surface CD25 antigen (IL-2 receptor-chain) at high
density.[1]
Early studies lacked the incorporation of
FoxP3+
, which has been recognized as a master
regulation and lineage-specification factor for Tregs.[1]
More recently, studies have shown that reciprocal
expression of the IL-7 receptor (CD127) on FoxP3+
Tregs is a more specific way to quantify Tregs. nTregs
constitute approximately 5%–10% of the peripheral
CD4+
T cell population in normal naive mice and
healthy humans and are characterized by the
constitutive expression of CD25 (IL-2 receptor chain)
and low expression levels of CD45RB. The
CD4+
CD25+
phenotype of Tregs has been insufficient
to define them as CD25, is not T cell restricted and
cannot be used to distinguish Tregs from effector T
cells (Teffs). While in murine models, CD4+
CD25+
population is highly enriched in Tregs, but in humans
CD25+
cells contain both T regulatory cells and effector
T cells populations.
To obtain enriched Tregs with little T effector cell
contamination, it is necessary to gate on the
CD4+
CD25+
high population that has regulatory
activity.[2]
This population accounts for only 1%–3% of
human CD4+
CD25+
Tcells. The CD4+
CD25+
CD127
low population contains approximately 80% of the
FoxP3+
cells and is significantly larger than the
CD4+
CD25+
high population. Overall, the available
data indicates that FoxP3+
identifies a broader Treg
population than that defined by CD4+
CD25+
or
CD4+
CD25+
CD127 low expression alone.
A definition of Tregs by combining CD127+
and
FoxP3+
has the advantage of including not only Tregs
expressing high levels of CD25+
but also Tregs with
low CD25+
expression and excluding at the same time
activated conventional T cells.[3]
While a strong
correlation between FoxP3+
and CD25+
expression in
the resting CD4+
T cell population has been reported,
low levels of FoxP3+
are detectable in CD25+
CD4+
T
cells. Thus, it seems that FoxP3+
expression too, in
humans, might not be confined to Tregs. Other cell-
surface markers associated with the phenotype and
function of Tregs are CTLA-4, CD62 ligand (CD62L),
TGF, IL-10, lymphocyte activation gene-3 (LAG-3),
integrin E7 (CD103), neuropilin-1 (Nrp1).
CONTROL OF T CELL RESPONSES BY
REGULATORY T CELLS
There are two categories of CD4+
CD25+
Tregs, which
differ in their origin, antigen specificity and effector
mechanism. One subset of Tregs develops during the
normal process of T cell maturation in the thymus,
resulting in the generation of a naturally occurring
population of CD4+
CD25+
Tregs (nTregs) that survive
in the periphery and poised to prevent potential
autoimmune responses. The second subset of induced
CD4+
CD25+
Tregs (iTregs) whose precursor is also
thymically derived, develops as a consequence of ex
vivo peripheral activation of classical naive
CD4+
CD25+
T cell populations under particular
conditions of suboptimal antigen exposure and/or co-
stimulation. This figure depicts a model of peripheral T
cell immunoregulation where the subset of nTregs can
work in synchrony with iTregs to control the activation
and function of adaptive immune responses. These
iTregs can be generated exvivo from mature
CD4+
CD25+
T cell populations under different
stimulatory conditions including antigen in the
presence of immunosuppressive cytokines, such as IL-
10 and TGF, vitamin D3 and dexamethasone, CD40-
CD40L blockade or immature dendritic cell
populations. iTregs function in vitro and in vivo
generally in a cytokine-dependent manner. In vitro,
CD4+
CD25+
nTregs are anergic to T cell receptor
(TCR) stimulation, but require activation via the TCR
to exert their regulatory functions. Once activated, they
suppress both CD4+
and CD8+
T cell responses in an
antigen non-specific manner.
GRAFT -VERSUS- HOST DISEASE
Graft-versus-host disease (GVHD), a major
complication following allogeneic hematopoietic stem
cell transplantation, is mediated by donor-derived T
cells. On activation with alloantigens expressed on host
antigen-presenting cells, naive CD4+
T cells
differentiate into T-helper cell subsets of effector T
cells expressing distinct sets of transcriptional factors
and cytokines. Classically, acute GVHD was suggested
to be predominantly related to Th1 responses.
However, a different and complex process involving
possible roles of newly identified Th17 cells as well as
Tregs in GVHD. Accumulating data from experimental
and clinical studies suggest that the fine balance
between Th1, Th2, Th17 and Tregs after
4. konakalla manikanta et al., / Journal of Pharmacreations Vol-2(1) 2015 [1-9]
4
transplantation may be an important determinant of the
severity, manifestation and tissue distribution of
GVHD.[5]
Understanding the dynamic process of
reciprocal differentiation of regulatory and T-helper
cell subsets as well as their interactions will be
important in establishing novel strategies for
preventing and treating GVHD.
HEMATOPOIETIC STEM CELL
TRANSPLANTATION
Allogeneic hematopoietic stem cell transplantation
(HCT) is a curative therapy for many hematologic,
some epithelial malignancies, and a variety of non-
malignant diseases. Hematopoietic stem cell
transplantation represents the most effective treatment
for patients with high risk and relapsed hematologic
malignancies. However, donor T cells included in the
graft react with recipient alloantigens present on APCs
(antigen presenting cells) and produce a syndrome
consisting of diarrhoea, weight loss, skin changes, and
liver abnormalities called GVHD. Despite the
enormous potential of hematopoietic stem cell
transplantation, the risks associated with GVHD limit
its extensive application.[6]
Billingham, an early pioneer in the field of bone
marrow transplantation (BMT), described three
requirements for the development of GVHD. First, the
donor graft must contain immunologically competent
cells (mature T cells). It was seen in both experimental
and clinical allogeneic BMT that the severity of GVHD
correlates with the number of donor T cells transfused.
Second, the recipient must be immune-compromised
and incapable of rejecting the transplanted cells. And,
finally the recipient must express tissue antigens that
are not present in the transplant donor.
DIRECT AND INDIRECT PRESENTATION
After allogeneic HCT transplants, both host- and
donor-derived APCs are present in secondary lymphoid
organs.[7]
The donor T cells that are included in the
graft recognize host alloantigens that are presented by
either host APCs (direct presentation) or donor APCs
(indirect presentation).
In the case of direct presentation, the donor T cells
recognize either peptide bound to allogeneic (MHC)
molecules or allogeneic MHC molecules without
peptide, whereas in indirect presentation, T cells
respond to the peptide generated by degradation of the
allogeneic MHC molecules which are presented on
self-MHC.[8]
It was previously reported that host APCs,
rather than donor APCs, are important for GVHD
induction in MHC mismatch.[9]
Studies indicate that presentation of distinct target
antigens by the host and donor type APCs might play a
differential role in mediating damage to target
organs.[10]
Additionally, recent findings indicate that
alloreactive Tregs specific for both directly and
indirectly presented alloantigens are required for the
induction of tolerance in organ transplantation.[11]
REGULATORY T CELLS: CELLULAR
THERAPEUTIC FOR GVHD
Studies conducted with mixed lymphocyte reaction
(MLR) experiments with both mouse and human cells
demonstrate the ability of regulatory T cells to suppress
the proliferative responses of alloreactive CD4+
T
cells.[12]
It was reported that Tregs are effective in
suppressing autoimmune diseases as well as solid organ
transplantation.[13]
These findings lead researchers to investigate the role
of Tregs in GVHD.[14]
It was initially reported that
depletion of CD4+
CD25+
T cells from the donor graft
accelerated GVHD and increased lethality.[15]
Additionally; Tregs have been reported to be effective
in preventing the development of GVHD across major
and minor MHC barriers in various HCT models.[16]
These studies demonstrate an important role of Tregs in
the development of GVHD.[17]
However, even though physiological levels of
endogenous CD4+
CD25+
T cells may contribute to the
development and course of GVHD, their small number
is likely insufficient to control the overwhelming
alloreactive T cell responses involved in major MHC
(major histocompatability) mismatched BMT
settings.[17]
Furthermore, the use of Tregs in allogeneic HCT is
very promising since it was reported that the Tregs can
suppress GVHD while preserving the GVL activity.
However, three major issues still hinder the
implementation of Tregs as immunotherapy in the
clinic. These include the low circulating numbers of
Tregs in the peripheral blood, the loss of suppressor
activity following ex vivo expansion and the lack of
Treg-specific markers to purify ex vivo expanded
Tregs.[17]
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5
However, the in vivo dynamics of Tregs trafficking
and survival predict effective strategies to control
GVHD after allogeneic transplantation.[18]
Despite
these considerations, several clinical trials are ongoing
that adoptively transfer Tregs as immunotherapy to
prevent the development of GVHD. One group has
transplanted freshly isolated donor Tregs while a
second group has expanded Tregs from cord blood with
anti-CD3 and anti-CD28 coated micro beads and
utilized them in double umbilical cord blood
transplantation.[19]
Figure 1 .Regulatory T cells can control immune responsiveness in vivo.
CD4+
CD25+
T cells have been shown to regulate
immune responses in vivo. This might be the result of
the suppressive effects of regulatory T cells on effector
T cells directly or on antigen-presenting cells (APCs).
This can be beneficial to the host by preventing
autoimmunity and enabling tolerance to organ, tissue
and cell transplants to develop. However, it can also be
detrimental as T regulatory cells can prevent effective
immune responses to tumors and infectious agents.
Tregs and GVHD
Preclinical murine transplantation models have
convincingly established that Tregs have the capacity
to prevent alloreactive T-cell responses and
experimental GVHD.[19]
Although the early data on
human Tregs and allo-HCT were mixed, the majority
of recent studies support a role for Tregs in the
protection from GVHD.[20]
For example, stem cell
grafts with a higher content of Tregs have been
correlated with less GVHD. Likewise, more rapid
Tregs reconstitution is associated with less GVHD,
whereas patients with delayed Treg recovery have a
higher likelihood of GVHD.[21]
Regulatory T cells are considered as candidates for
immunotherapy after BMT (bone marrow
transplantation) as they may reduce GVHD while
maintaining Graft versus leukemia effects. Regulatory
T cells (Tregs) play a vital role in the homeostasis of
the immune system and in the modulation of the
immune response. Tregs have emerged as key players
in the development and maintenance of peripheral
immune tolerance. [22]
Naturally occurring thymus-derived CD4+
CD25+
Tregs
are a subset of T cells which have immunosuppressive
properties and are 5%–10% of the total peripheral
CD4+
T cells. In normal conditions, Tregs regulate
ongoing immune responses and prevent autoimmunity.
Imbalanced function or number of these cells, either
enhanced or decreased, might lead to tumor
development and autoimmunity, respectively. These
cells thus play a major role in autoimmune diseases,
transplantation tolerance, infectious diseases, allergic
disease and tumour immunity.[23]
These natural properties make Tregs attractive tools for
novel immunotherapeutic approaches. The in vivo
manipulation or depletion of Tregs may help devise
effective immunotherapy for patients with cancer,
autoimmunity, graft versus-host disease, infectious
diseases and allergic diseases. It is crucial to
understand the biology of Tregs before attempting
therapies, including (i) the injection of expanded Tregs
to cure autoimmune disease or prevent graft-versus-
host disease or (ii) the depletion or inhibition of Tregs
in cancer therapy. Recent findings in murine models
and studies in humans have opened new avenues to
study the biology of Tregs and their therapeutic
potential. This overview provides a framework for
integrating these concepts of basic and translational
research.[23]
REGULATORY T CELL- MEDIATED
SUPPRESSION
Tregs are able to suppress the proliferation, activation
and cytokine production of conventional T cells.
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6
Multiple mechanisms of suppression by Treg have been
identified which can be divided into four categories: (1)
cell-cell contact, (2) secretion of suppressive factors,
(3) competition for IL-2, and (4) modulation of APC by
Treg.
Cell-cell contact
Tregs can suppress effector T cells (Teff) directly via a
cell-cell contact-dependent mechanism, as suppressive
activity in vitro is abrogated when responder T cells
and Tregs are physically separated by a Transwell
membrane insert.[24]
It has been suggested that contact-
dependent suppression is mediated by TGF, as murine
and human Tregs express membrane-bound TGF
suppression is abolished in the presence of anti-TGF-
beta.[25]
However, Tregs isolated from neonatal TGF-
beta knockout mice exhibit normal suppressive activity
in vitro. Contact-dependent suppression may also be
mediated by the modulation of the level of cyclic
adenosine monophosphate (cAMP) in T cells.[26]
Tregs
can deliver cAMP directly to the T cells via gap-
junctions and thereby inhibit their proliferation and
differentiation and cause selective inhibition of
cytokine gene expression. Activated Tregs can also kill
activated T cells by perforin, granzyme, or Fas-
dependent mechanisms.[27]
Secretion of suppressive factors
Neutralizing in vitro antibodies to IL-10 or TGF not
block Tregs activity and Tregs from mice lacking IL-10
and TGF-b show similar suppressive activity. In
contrast, in certain in vivo models, TGF-beta and IL-10
are active players in the effector function of Treg.[28]
IL-35 may contribute to the suppressive function of
murine Tregs in vitro and in vivo as Treg from IL-35
mice have significantly reduced regulatory activity in
vitro and fail to control homeostatic proliferation and to
cure inflammatory bowel disease in vivo.[29]
Furthermore, ectopic expression of IL-35 confers
regulatory activity on naive T cells, whereas
recombinant IL-35 suppresses T cell proliferation.
Finally, Tregs can also convert extracellular 5’-AMP
(adenosine mono phosphate) to adenosine via the
ectonuclidases CD73+
and CD39+
expressed on their
cell surface.[30]
Binding of adenosine to the adenosine
A2A receptor on T cells increases intracellular cAMP
levels. Tregs from CD39+
mice show impaired
suppressive properties in vitro and fail to block
allograft rejection in vivo.[31]
Competition for IL-2
Local competition for IL-2, because Tregs
constitutively express the IL-2 receptor CD25+
, it was
suggested that Tregs suppress T cell responses by
competing for IL-2 produced by effector T cells. By
consuming the available IL-2, Tregs would prevent
Teff (T effector cells) proliferation and
differentiation.[32]
In agreement with this, blocking of IL-2 uptake in
Tregs by selective inhibition of their IL-2 receptor
completely abrogates their suppressive function.[33]
Furthermore, the effects of Tregs on T cells can be
mimicked by anti-IL-2. However, Tregs suppression
cannot be entirely explained by the competitive
consumption of IL-2 as Tregs can efficiently suppress
proliferation of IL-2-receptor deficient T cells in
vitro.[34]
Modulation of APC by Treg
Apart from direct interactions with T cells, Tregs can
inhibit immune responses through modulation of major
subpopulations of APC, i.e., B cells, monocytes or
macrophages and most importantly; dendritic
cells(DC).[35]
DC constitute a heterogeneous population
of professional APC that have the potential to induce
immunity or tolerance depending on the state of
activation, activation signals and cytokine milieu.[36]
DC exposed to Treg down regulate their antigen
presenting function by reducing the expression of MHC
class II and the co-stimulatory molecules CD80+
and
CD86+
. The interaction between CTLA-4 on Treg and
CD80/86 on DC can induce the expression of the
suppressive mediator indoleamine 2, 3-dioxygenase
(IDO) by DC.[37]
Indoleamine 2, 3-dioxygenase
catalyzes the breakdown of tryptophan into kynurenine
and other catabolites, which have potent
immunosuppressive effects in the local
microenvironment of DC. Furthermore, DC can up
regulate immunosuppressive molecules like B7-H3 and
B7-H4 after interaction with Tregs, which results in
reduced T cell stimulatory capacity. Interaction
between Tregs and DC can also result in the secretion
of the immunosuppressive cytokine IL-10 by the latter,
which exerts suppressive effects on T lymphocyte
proliferation.[38]
Altogether, these data demonstrate that
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7
Tregs inhibit DC activation and induce inhibitory DC,
which are ineffective in activating Teff cells.
However, DC are not absolutely required for Tregs
suppressor function, at least in vitro, since Tregs keep
their suppressive capacity in DC-free systems.[39]
Although several mechanisms of suppression have
been described, it is still unclear which mechanisms
contribute to Tregs-mediated suppression in vivo.[40]
Most likely, Tregs do not rely on just one mechanism,
but use different mechanisms simultaneously
depending on environmental factors and the site of
action.
TREG-MEDIATED SUPPRESSION: A SITE
OF ACTION
To modulate immune responses in vivo, appropriate
trafficking and retention of Tregs to specific sites is
required. Tregs have been identified in lymphoid
tissues, including thymus, spleen and lymph nodes, in
peripheral blood as well as within various peripheral
sites, including inflamed organs, tumors and infectious
sites.[41]
In order to enter all these sites, Tregs must
express a variety of chemokine receptors and tissue-
specific homing receptors that guide their migration to
specific tissues. Some Treg subsets appear to be
specialized in inhibiting the initiation of the immune
response within lymphoid tissues, like Treg expressing
the lymph node homing receptor CD62L and
chemokine receptor CCR7.[42]
Other Treg subsets may limit peripheral expansion,
cytokine secretion or cytolytic function of Teff cells at
the effector site, like in inflamed tissues.[43]
These Treg
might include subsets expressing tissue-specific
adhesion molecules and chemokine receptors like the
inflammatory chemokine receptor CCR2 or CCR5, or
the aE-integrin CD103.[44]
Recently demonstrated that
Treg sequentially migrate from inflamed tissues to the
draining lymph node and that this migration pattern is
necessary for the optimal suppressive function of Treg
and islet graft survival .Whether Treg also follow this
migration pattern during the course of other immune
responses remains to be determined.[45]
CONCLUSION
Based on this review, infusion of donor T regulatory
cells with conventional T cells reduces the graft-versus-
host disease and enhances the immune recovery in
high-risk leukemia patients.
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