Regulation of immune response Immunotolerance.pdf

Regulation of immune response - Immunotolerance George Nadăș,Professor of Immunology, [email protected] Selffromnonself Immunotolerance Overview Of Immunologic Tolerance Immunologic tolerance - unresponsiveness to an antigen that is induced by exposure to that antigen The term arose from the exper...

Regulation of immune response - Immunotolerance George Nadăș,Professor of Immunology, [email protected] Selffromnonself Immunotolerance Overview Of Immunologic Tolerance Immunologic tolerance - unresponsiveness to an antigen that is induced by exposure to that antigen The term arose from the experimental observation that animals that had encountered an antigen under particular conditions would not respond to, that is, would tolerate, subsequent exposures to the same antigen When specific lymphocytes encounter antigens, the lymphocytes may be activated, leading to immune responses, or the cells may be inactivated or eliminated, leading to tolerance The same antigen may induce an immune response or tolerance, depending on the conditions of exposure and the presence or absence of other concomitant stimuli such as costimulators 2 Immunotolerance Overview Of Immunologic Tolerance Antigens that induce tolerance are called tolerogens, or tolerogenic antigens, to distinguish them from immunogens, which generate immunity Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases self–non-self discrimination = the ability of the immune system to recognize and respond to foreign antigens but not to self antigens 3 Immunotolerance Overview Of Immunologic Tolerance The mechanisms of tolerance eliminate and inactivate lymphocytes that express high-affinity receptors for self antigens All individuals inherit essentially the same antigen receptor gene segments, and these recombine and are expressed in lymphocytes as the cells arise from precursor cells during this process of generating a large and diverse repertoire, some developing T and B cells in every individual may express receptors capable of recognizing normal molecules in that individual (i.e., self antigens) The mechanisms of immunologic tolerance prevent such reactions 4 Immunotolerance Central and peripheral tolerance Tolerance is antigen specific, resulting from the recognition of antigens by individual clones of lymphocytes This contrasts with therapeutic immunosuppression, which affects lymphocytes of many specificities Self-tolerance may be induced in immature selfreactive lymphocytes in the generative lymphoid organs (central tolerance) Takes marrow thymus placeinbone lymphocytes in peripheral or sites in mature (peripheral tolerance) Yong responsive 5 Immunotolerance Central tolerance Central tolerance ensures that the repertoire of mature naive lymphocytes becomes incapable of responding to self antigens that are expressed in the generative lymphoid organs (the thymus for T cells and the bone marrow for B lymphocytes, also called primary or central lymphoid organs) Central tolerance occurs during a stage in the maturation of lymphocytes when an encounter with an antigen may lead to cell death or replacement of a self-reactive antigen receptor with one that is not self-reactive Central tolerance is not perfect, and many self-reactive lymphocytes complete their maturation and are present in healthy individuals. Therefore, the mechanisms of peripheral tolerance are needed to prevent activation of these potentially dangerous lymphocytes 6 Immunotolerance Peripheral tolerance Mature lymphocytes that recognize self antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis These mechanisms of peripheral tolerance are important for maintaining unresponsiveness to self antigens that are expressed in peripheral tissues and not in the generative lymphoid organs and for tolerance to antigens that are expressed after mature lymphocytes specific for these antigens have already been generated Peripheral tolerance is also maintained by regulatory T cells (Tregs) that actively suppress the activation of lymphocytes specific for self and other antigens 7 T L y m p h o c y t e To l e r a n c e Central T Cell Tolerance During their maturation in the thymus, many immature T cells that recognize antigens with high avidity die, and some of the surviving cells in the CD4+ lineage develop into Tregs Death of immature T cells as a result of recognition of antigens in the thymus is known as deletion, or negative selection 8 T L y m p h o c y t e To l e r a n c e Central T Cell Tolerance This process affects class I and class II major histocompatibility complex (MHC)- restricted T cells and is therefore important for tolerance in both CD8+ and CD4+ lymphocyte populations Negative selection of thymocytes is responsible for the fact that the repertoire of mature T cells that leave the thymus and populate peripheral lymphoid tissues is unresponsive to many self antigens that are present in the thymus Negative selection occurs in double-positive T cells in the thymic cortex and newly generated single-positive T cells in the medulla In both locations, immature thymocytes with high-affinity receptors for self antigens that encounter these antigens die by apoptosis 9 T L y m p h o c y t e To l e r a n c e Central T Cell Tolerance peripheral tissue antigens are produced in medullary (MTECs) thymic under autoimmune the regulator epithelial control (AIRE) cells of the protein autoimmune diseases This group of diseases is characterized by antibody- and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets, as well as the skin and other tissues 10 T L y m p h o c y t e To l e r a n c e Peripheral T Cell Tolerance The mechanisms of peripheral tolerance are: 1. anergy (functional unresponsiveness) 2. suppression by Tregs 3. deletion (cell death) 11 T L y m p h o c y t e To l e r a n c e 1. Anergy (Functional Unresponsiveness) Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen In anergy, the self-reactive cells are not killed, but they become unresponsive to the antigen full activation of T cells requires the recognition of the antigen by the TCR (which provides signal 1) and recognition of costimulators, mainly B7-1 and B7-2, by CD28 (signal 2) Prolonged signal 1 (i.e., antigen recognition) alone may lead to anergy 12 T L y m p h o c y t e To l e r a n c e 1. Anergy (Functional Unresponsiveness) Several mechanisms may function to induce and maintain the anergic state: 1) TCR-induced signal transduction is blocked in anergic cells 2) Self antigen recognition without costimulation may activate cellular ubiquitin ligases, which ubiquitinate TCR-associated proteins and target them for proteolytic degradation in proteasomes or lysosomes 3) When T cells recognize self antigens in the absence of innate immune responses, they may engage inhibitory receptors of the CD28 family, whose function is to terminate T cell responses 13 T L y m p h o c y t e To l e r a n c e 2. Suppression by Regulatory T Cells Regulatory T cells are a subset of CD4+ T cells whose principal function is to suppress immune responses CD4+ Tregs express high levels of the IL-2 receptor α chain (CD25) and the transcription factor called FOXP3 CD4+ FOXP3+ + CD25high 14 T L y m p h o c y t e To l e r a n c e 2. Suppression by Regulatory T Cells Generation and Maintenance of Regulatory T Cells Tregs are generated mainly by self antigen recognition in the thymus and also by recognition of self and foreign antigens in peripheral tissues Tregs can also develop after inflammatory reactions. The majority of Tregs in lymphoid tissues are thought to be derived from the thymus as a consequence of self antigen expression The generation, survival, and functional competence of Tregs are dependent on the cytokine IL-2 The generation of some Tregs requires the cytokine transforming growth factor-β (TGF-β) 15 T L y m p h o c y t e To l e r a n c e 3. Deletion of T Cells by Apoptotic Cell Death T lymphocytes antigens with that high recognize affinity or self are cqtdaki.i.rs repeatedly stimulated by antigens may die by apoptosis There are two major pathways of apoptosis: 1) mitochondrial (or intrinsic) pathway 2) death receptor (or extrinsic) pathway 16 T L y m p h o c y t e To l e r a n c e 3. Deletion of T Cells by Apoptotic Cell Death 1) mitochondrial (or intrinsic) pathway is regulated by the BCL-2 family of proteins, named after the founding member, BCL-2, which was discovered as an oncogene in a B cell lymphoma The pathway is initiated when cytoplasmic proteins of the BCL-2 family are induced or activated as a result of growth factor deprivation, noxious stimuli, DNA damage, or certain types of receptor-mediated signaling BCL-2 family proteins BAX and BAK insert into the outer mitochondrial membrane, leading to increased mitochondrial permeability As a result, cytochrome c and other pro-apoptotic mitochondrial preteins leak out into the cytosol and activate cytosolic enzymes called caspases – caspase 9 17 T L y m p h o c y t e To l e r a n c e 3. Deletion of T Cells by Apoptotic Cell Death 2) death receptor (or extrinsic) pathway cell surface receptors of the TNF receptor superfamily are engaged by their TNF superfamily ligands The receptors oligomerize and activate cytoplasmic adaptor proteins, which assemble procaspase-8, which cleaves itself when oligomerized and produces active caspase-8 The active caspase-8 cleaves downstream caspases, again resulting in apoptosis In T cells the most important death receptor is FAS (CD95), and its ligand is FAS ligand (FASL) FAS is a member of the TNF receptor family, and FASL is homologous to TNF 18 B L y m p h o c y t e To l e r a n c e Central B-cell tolerance Tolerance in B lymphocytes is necessary for maintaining unresponsiveness to T-independent self antigens, such as polysaccharides and lipids B cell tolerance also plays a role in preventing antibody responses to protein antigens During their maturation in the bone marrow, B lymphocytes first express IgM as their antigen receptor and are functionally immature at this stage If these B lymphocytes recognize self antigens in the bone marrow with high affinity, they either change their specificity (receptor editing) or are deleted 19 B L y m p h o c y t e To l e r a n c e Peripheral B-cell tolerance Mature B lymphocytes that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered anergic or die by apoptosis Several mechanisms of peripheral tolerance in B cells have been described: 1) Anergy 2) Deletion 3) Signaling by inhibitory receptors - CD22 4) Regulation of B cells by Tregs - subset of Tregs, called T follicular regulatory (Tfr) cells 20 Humoral immune response Summary Immunologic tolerance is unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen Tolerance to self antigens is a fundamental property of the normal immune system, and the failure of self-tolerance leads to autoimmune diseases Antigens may be administered in ways that induce tolerance rather than immunity, and this may be exploited for the prevention and treatment of transplant rejection and autoimmune and allergic diseases 21 Humoral immune response Summary Central tolerance is induced in the generative lymphoid organs (thymus and bone marrow) when immature lymphocytes encounter self antigens present in these organs Peripheral tolerance occurs when mature lymphocytes recognize self antigens in peripheral tissues under particular conditions In T lymphocytes, central tolerance occurs when immature thymocytes with highaffinity receptors for self antigens recognize these antigens in the thymus 22 Humoral immune response Summary Some immature T cells that encounter self antigens in the thymus die (negative selection), and others develop into FOXP3+ regulatory T lymphocytes (Tregs) that function to control responses to self antigens in peripheral tissues In CD4+ T cells, anergy is induced by antigen recognition without adequate costimulation or by engagement of inhibitory receptors such as CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein-1) 23 Humoral immune response Summary T cells that encounter self antigens without other stimuli or that are repeatedly stimulated may die by apoptosis In B lymphocytes, central tolerance is induced when immature B cells recognize multivalent self antigens in the bone marrow The result is the acquisition of a new specificity, called receptor editing, or apoptotic death of the immature B cells Mature B cells that recognize self antigens in the periphery in the absence of T cell help may be rendered anergic and ultimately die by apoptosis or become functionally unresponsive because of the engagement of inhibitory receptors 24 Immunotolerance ©2024 Ross University School of Veterinary Medicine. 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