Lecture 24: Regulation of Immune Responses in the Periphery (2024) PDF

Chapter 10: Regulation of immune responses in the periphery  Lecture outline T Lymphocyte Regulation T regulatory cells (Tregs) CD4 CD8 Immunosuppressive Molecules Immune Deviation Immune Privilege Intestinal Microflora Experimental To...

Chapter 10: Regulation of immune responses in the periphery  Lecture outline T Lymphocyte Regulation T regulatory cells (Tregs) CD4 CD8 Immunosuppressive Molecules Immune Deviation Immune Privilege Intestinal Microflora Experimental Tolerance  Regulation of lymphocyte responses Once lymphocytes are activated, various mechanisms in the periphery control the quality, intensity and duration of the resulting adaptive response. These mechanisms most often involve 1. Regulatory T cells, 2. Immunosuppressive molecules, 3. Immune deviation and/or 4. Immune privilege. Based on recent studies intestinal microflora has also been implicated in controlling peripheral tolerance in the gut.  Regulatory T cells (Treg) Regulatory T cells (Tregs) can control the responses of activated conventional T cells (including autoreactive effector T cells) regardless of antigenic specificity of T cells Tregs help to balance the host requirement for protective anti-pathogen & anti-tumor responses with its need to avoid excessive inflammatory & autoimmune responses.  Regulatory T cells (Treg) Aberrant activation of Th1 & Th17 cells is associated with chronic inflammation & autoimmune diseases. Similarly, inappropriate uncontrolled Th2 responses are linked to allergic inflammation & other hypersensitivities. In a healthy host, various subsets of Treg interact with conventional Th1, Th2 & Th17 cells to limit their activities. Multiple types of both CD4+ & CD8+ Tregs exist, but CD4+ Treg are better characterized.  CD4+ Regulatory T cells (Treg) There are four major subtypes of CD4+ Treg: – nTreg cells: derived directly from thymic precursors. – iTreg, Tr1 and Th3 cells: they are induced to differentiate from conventional T cells in secondary lymphoid tissues. These subsets differ with respect to their derivation, phenotypic markers, suppressive mechanisms and regulatory effects.  Thymus derived Treg (nTreg) The best documented CD4+ Tregs are called “natural Treg” or ‘nTreg’. nTreg population comprises about 6-10% of all peripheral CD4+ T cells in both healthy human & mice & display a TCR repertoire which is biased toward self-antigen. nTreg are characterized by expression of transcription factor Foxp3 & high levels of CD4 & CD25 (IL-2R alpha chain). nTreg develop from precursors in the thymus, like conventional T cells, & can first be identified at DP stage. Newly produced nTregs express many chemokine receptors that allows them to recirculate through secondary lymphoid tissues, migrate to GALT, & take up residence in any peripheral tissue.  Thymus derived Treg (nTreg) nTreg cell has capacity to block proliferation & IL-2 production of conventional CD4+ T cells of any antigenic specificity. These suppressive effects are not cytokine-mediated but rather require direct intercellular contact that is independent of the TCRs of both T cells. In some cases, apoptosis of conventional T cell is induced by Fas-FasL interaction. In other cases, T cell death is mediated by high concentration of negative regulators CTLA-4 & PD-1 on Treg. nTreg may have direct effects on APCs & cause APCs to become tolerogenic.  Induced Regulatory T cells (iTreg) The interaction of naïve T cells with tolerogenic DCs can result in iTreg differentiation, depending upon the cytokines in the immediate microenvironment. As discussed earlier, Th0 cells that interact with a mature DC in a lymphoid microenvironment rich in TGF-beta and IL-2 can give rise to ‘induced Treg” (iTreg) cells. Like nTreg, iTreg cells express CD4, CD25 and Foxp3. However, iTreg cells suppress effector T cell via secretion of the immunosuppressive cytokines IL-10 and TGF-b rather than intercellular contacts. Both IL-10 and TGF-b from iTreg can also attenuate DC functions, allowing iTregs to inhibit naïve T cell activation.  Tr1 and Th3 cells Most Tr1 & Th3 cells arise from naïve T cells (not Th0 cells) that interact with tolerogenic DCs in a lymphoid environment that is devoid of DAMPs/PAMPs but rich in IL- 10 and/or TGF-b. Under these conditions, naïve T cell is not anergized or deleted but instead proliferates & differentiates into Tr1 cells (If IL-10 is dominant) or Th3 (if TGF-b is dominant) Other Tr1 & Th3 cells may arise from a naive T cells that establishes intercellular contacts with an nTreg cell. Like iTreg cells, Tr1 and Th3 cells shut down activated effector T cells in an antigen non-specific manner by secreting immunosuppressive cytokines.  Tr1 and Th3 cells Tr1 cells secrete IL-10 plus low amount of TGF-b while Th3 cells preferentially secret TGF-b. Tr1 cells express low levels of both CD25 and CTLA-4, whereas Th3 cells express low level of CD25 and moderate level of CTLA-4. Unlike nTreg & iTreg, neither Tr1 nor Th3 cells express Foxp3. Fig 10.4: Influence of DC status on T cell activation, regulation and tolerance. Regulatory T cells  CD8+Regulatory T cells (Treg) Natural and induced subsets of CD8+ Treg also exist in humans and mice. These subsets express both Foxp3 & CD25, but various subtypes of these cells are distinguished by expression of other surface markers ( such as CTLA4, CD28, & CD122). Some CD8+ Treg block the proliferation of conventional naïve and effector T cells via direct intercellular contacts whereas other CD8+ Tregs secrete IL-10 and/or TGF-beta. Still other CD8+ Tregs subsets exert their primary effects on APCs by making APCs tolerogenic. Thus, although there is general overlaps of CD8+ Tregs in function with CD4+ Treg, some Tregs play a unique role under certain circumstances.  Immunosuppressive molecules Certain cytokines particularly IL-10 & TGF-b have immunosuppressive effects on innate & adaptive immune responses, including those initiated against self Ags. Immunosuppressive cytokines are mostly produced by innate leukocytes activated by a pathogen, but they are also produced by CD4+ iTreg, CD8+iTreg, Th3 & Tr1 cells. IL-10 downregulates TCR-induced intracellular signaling; inhibits macrophage activation & inflammatory cytokine secretion; blocks APC function; blocks Th cells proliferation; & destabilizes mRNAs of many cytokines including IL-2.  Immunosuppressive molecules Lack of IL-2 compromises signal 3 delivery & thus promotes T cell anergization. TGF-b inhibits macrophage and NK cell activation; blocks proliferation & IL-2 production of activated T cells, downregulates Ig synthesis & interferes with stimulatory effects of IL-2 on T & B cells.  Immune deviation Immune deviation: a phenomenon in which an adaptive response that has the potential to cause direct or indirect tissue damage is converted to a less harmful response. It is caused by a bias toward the differentiation of a specific type of effector Th cell following the activation of a Th0 cell.  Immune deviation Depending on the tissue involved, the differentiation of one particular subset can avoid potential damage that might have been mediated by differentiation of another subset. Example: Eye tissues are very sensitive to Th1 responses. Factors within the microenvironment of the eye, therefore, direct Th2 responses. Thus, the immune response in eye is still present, but its effects have been blunted by ‘deviating’ effector generation toward Th2 phenotype.  Immune privilege Sites with immune privilege are anatomical regions that are naturally less subject to immune responses than most other areas of the body. Immune–privileged sites include the central nervous system and brain, the eyes and the testes. Even foreign Ags accessing these tissues do not generally trigger immune responses. Immune privilege is thought to exist because the collateral damage accompanying typical immune responses would irreparably damage these highly sensitive tissues. Fas-FasL interactions, immunosuppressive cytokines, immune deviation and the action of regulatory T cells contribute to immune privilege.  Intestinal microflora It is well known that innate and adaptive leukocytes in a healthy gut do not mount aggressive inflammatory responses against the intestinal microbiota. It is well established that commensal bacteria are critical for maintaining overall gut immune homeostasis and oral tolerance to food Ags. The gut microbes have particular effects on both DCs and regulatory T cells.  Intestinal microflora DCs that interact with certain species of commensal bacteria are rendered tolerogenic & steer differentiation of Th0 cells towards Treg rather than effector T cells. Gut commensals also have direct effects on Tregs, promoting their accumulation and influencing their cytokine production profiles and this results in an anti-inflammatory microenvironment in the healthy gut. Alterations in normal gut microbiota can trigger autoimmune and inflammatory gut disorders such as colitis & Crohn’s disease. Experimental tolerance Read the details from the textbook under sub-heading ‘characteristics of tolerogens’ (page 241-243).  Next Lecture Chapter 11 – NK, gd T and NKT cells.