Chapter 10.


             T-cells &
       Immunological Tolerance




                  Tolerance                       ...
TOLERANCE                                              TOLERANCE
Introduction                                           • ...
Ignorance                                               Ignorance
•       It can be shown that there are T cells and B    ...
Mechanism of tolerance induction                   Mechanism of tolerance induction
                                      ...
Dendritic cells: regulators of alloimmunity and
    opportunities for tolerance induction
  •   Dendritic cells (DCs) are ...
Oral tolerance                                        Oral tolerance
•   Antigens might be taken up by Microfold cells
   ...
T regulatory cell family                               T regulatory cell family
•   However, it should be mentioned that t...
History                                                 History

•   Burnet postulated that there was a temporal
    windo...
History
•   I believe that the supposed conflict between
    Matzinger and Medewar is rather 'hyped up' and
    essentiall...
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Microsoft PowerPoint - No_13_Immunological_Tolerance

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Microsoft PowerPoint - No_13_Immunological_Tolerance

  1. 1. Chapter 10. T-cells & Immunological Tolerance Tolerance Tolerance • Our own bodies produce some 100,000 different proteins and one of the longstanding • The mechanisms the immune system uses conundrums of immunology has been to to ensure the absence of self-reactivity understand how the immune system (autoimmunity) include: produces a virtual repertoire against pathogens while at the same time avoiding • Central Tolerance - this occurs during reacting to self. lymphocyte development. • The strict definition of immunological • Peripheral Tolerance - occurs after tolerance occurs when an immunocompetent lymphocytes leave the primary lymphoid host fails to respond to an immunogenic organs. challenge with a specific antigen. Central Tolerance Peripheral Tolerance 1
  2. 2. TOLERANCE TOLERANCE Introduction • Tolerance is different from non-specific • Tolerance refers to the specific immunosuppression and immunodeficiency. immunological non-reactivity to an antigen It is an active antigen-dependent process in resulting from a previous exposure to the response to the antigen. same antigen. • Like immune response, tolerance is specific • While the most important form of tolerance and like immunological memory, it can exist in T-cells, B cells or both and like is non-reactivity to self antigens, it is immunological memory, tolerance at the T possible to induce tolerance to non-self cell level is longer lasting than tolerance at antigens. When an antigen induces the B cell level. tolerance, it is termed tolerogen. Tolerance to tissues and cells Tolerance to soluble antigens • Tolerance to tissue and cell antigens can be • A state of tolerance to a variety of T- induced by injection of hemopoietic (stem) cells dependent and T-independent antigens in neonatal or severely immunocompromised (by has been achieved in various experimental lethal irradiation or drug treatment) animals. models. • Also, grafting of allogeneic bone marrow or thymus in early life results in tolerance to the • Based on these observations it is clear donor type cells and tissues. Such animals are that a number of factors determine known as chimeras. These findings are of whether an antigen will stimulate an significant practical application in bone marrow immune response or tolerance grafting. Tolerance Tolerance • Induction of tolerance in T cells is easier and requires relatively smaller amounts of tolerogen than tolerance in B cells. • Maintenance of immunological tolerance requires persistence of antigen. • Tolerance can be broken naturally (as in autoimmune diseases) or artificially (as shown in experimental animals, by x- irradiation, certain drug treatments and by exposure to cross reactive antigens). Also see Table 10-1 of text 2
  3. 3. Ignorance Ignorance • It can be shown that there are T cells and B • The first is that the antigen may simply be cells specific for auto-antigens present in present in too low concentration. Since all circulation. lymphocytes have a threshold for receptor • These cells are quite capable of making a occupancy which is required to trigger a response but are unaware of the presence of response then very low concentrations of their auto-antigen. This arises for 2 reasons. antigen (in the case of T cells these are very low, see below) will not be sensed. Ignorance Mechanism of tolerance induction • The second possibility is a more interesting one. Some antigens are sequestered from the Clonal deletion: immune system in locations which are not freely • Functionally immature cells of a clone exposed to surveillance. encountering antigen undergo a programmed • These are termed immunologically privileged sites. Examples of such sites are the eye, CNS cell death, as auto-reactive T-cells are and testis. eliminated in the thymus following interaction • Pathologically mediated disruption of these with self antigen during their differentiation privileged sites may expose the sequestered (negative selection). antigens leading to an autoimmune response. Mechanism of tolerance induction Mechanism of tolerance induction Clonal deletion: Clonal anergy: • Likewise, differentiating early B cells become • Auto-reactive T cells, when exposed to tolerant when they encounter cell-associated antigenic peptides which do not possess co- or soluble self antigen. stimulatory molecules (B7-1 or B7-2), become anergic to the antigen. • Clonal deletion has been shown to occur also in the periphery. 3
  4. 4. Mechanism of tolerance induction Mechanism of tolerance induction Receptor editing: Clonal anergy: • B cells which encounter large amounts of • Also, B cells when exposed to large amounts soluble antigen, as they do in the body, and of soluble antigen down regulate their bind to this antigen with very low affinity surface IgM and become anergic. These become activated to re-express their RAG-1 cells also up-regulate the Fas molecules on and RAG-2 genes. their surface. An interaction of these B cells • These genes cause them to undergo DNA with Fas-ligand-bearing cells results in their recombination and change their antigen death via apoptosis. specificity. What are RAG-1 RAG-2? • Recombination signal sequences (RAG). RAG-1/RAG-2 • RAG-1 is a specific endonuclease and is only active when complexed with RAG-2. • Specific DNA sequences (heptamers) found adjacent to the V, D, and J segments in the antigen receptor loci and recognized by the RAG-1/RAG-2 component of the V(D)J recombinase. (see figure 7-11) Mechanism of tolerance induction Mechanism of tolerance induction Anti-idiotype antibody: Termination of tolerance • Anti-idiotype antibodies produced experimentally • Experimentally induced tolerance can be have been demonstrated to inhibit immune response to specific antigens. terminated by prolonged absence of exposure to • Anti-idiotype antibodies are produced during the the tolerogen, by treatments which severely process of tolerization. damage the immune system (x-irradiation) or by • Such antibodies may respond to the unique immunization with cross reactive antigens. receptors of other lymphocytes and serve to shut • These observations are of significance in the off antigen specific responses. conceptualization of autoimmune diseases. • Therefore, these antibodies prevent the receptor from combining with antigen. 4
  5. 5. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction • Dendritic cells (DCs) are uniquely well- equipped antigen-presenting cells (APCs) regarded classically as sentinels of the Regulatory T cells immune response, which induce and regulate T-cell reactivity. • They play critical roles in central tolerance and in the maintenance of peripheral tolerance in the normal steady state. Mechanism of tolerance induction Regulatory T cells Suppressor cells: • CD4+ T lymphocytes that express high • Both low and high doses of antigen may levels of IL-2r α chain (CD25) but not other markers of activation. induce suppressor T cells (Regulatory T cells) which can specifically suppress • Regulatory T cells may be generated by self antigen recognition in the thymus or in immune responses of both B and T cells, the periphery. either directly or by production of cytokines, most importantly, TGF-β and IL- • These cells induce immunosuppression by secreting TGF-β and IL-10 and thereby 10. inhibit Mφ function and IFN-γ activity. Fig 10-10 Oral tolerance • The gastrointestinal tract is the largest immunologic organ in the body. • It is constantly bombarded by a myriad of dietary proteins. • Despite the extent of protein exposure, very few patients have food allergies because of development of oral tolerance to these antigens. • Once proteins contact the intestinal surface, they are sampled by different cells and, depending on their characteristics, result in different responses. 5
  6. 6. Oral tolerance Oral tolerance • Antigens might be taken up by Microfold cells overlying Peyer's patches, dendritic cells, or epithelial cells. • Different cells of the immune system participate in oral tolerance induction, with regulatory T cells being the most important. • Several factors can influence tolerance induction. • Some are antigen related, and others are inherent to the host. Disturbances at different steps in the path to oral tolerance have been described in food hypersensitivity. T regulatory cell family T regulatory cell family • The idea of specific suppressor T cell populations that counteract harmful autoaggressive immune responses in the • In 1995 Sakaguchi et al. described for the periphery was first described in the 1970s first time a subpopulation of CD4+ T helper by Gershon et al. cells, characterized by a constitutive expression of the IL-2 receptor α-chain • However, at that time neither the cells nor (CD25), that is essential to control the hypothetical soluble suppressor factors autoaggressive immune responses in mice. responsible for the observed effects could be identified. T regulatory cell family T regulatory cell family • After subsequent in vitro studies by several • They represent 5–10% of all peripheral groups, this population is now referred to as CD4+ T cells. CD4+CD25+ T regulatory cells (Tregs). • Freshly isolated CD25+ Tregs do not • This distinct T cell population was originally proliferate after allogeneic or polyclonal described in mice. However, comparable T activation in vitro, but Tregs suppress the cell suppressor populations, with identical activation and cytokine release of CD4+ and phenotype and functional activities have CD8+ T cells in an antigen-nonspecific and been defined more recently in rats and cell contact-dependent manner. humans. 6
  7. 7. T regulatory cell family T regulatory cell family • However, it should be mentioned that the • In the human immune system, two distinct subsets of resident CD25+ Tregs can be activation of Tregs is also antigen-specific. distinguished based on the expression of distinct • The main mechanism of suppression integrins. seems to be the inhibition of IL-2 • Tregs expressing the α4 β7 integrin can convert transcription in the responder T cell CD4+ T cells into IL-10-producing Tr1-like cells, whereas α4 β1+ Tregs induce TGF-β -producing population. Th3-like cells. • Nevertheless, the molecules involved in this • The integrins α4 β1 and α4β7 are homing cell contact-dependent suppression are still receptors for cellular migration of T lymphocytes largely unknown. to inflamed tissues and to mucosal sites, respectively. T regulatory cell family T regulatory cell family • The α4β1-integrin binds to VCAM1 (vascular cell adhesion molecule-1), which is induced on the endothelium of inflamed tissues, whereas the α4β7-integrin binds to vascular addressins, selectively expressed by venules in mucosal tissues. • Therefore, it can be postulated that α4β1+CD25+ Tregs migrate in vivo to inflamed tissues where they can inhibit effector T cell responses. α4β7+CD25+ Tregs are specialized to migrate to mucosal tissues, to counteract autoreactive T cells, thereby preventing chronic mucosal inflammations. History of Tolerance Timing • Some 50 years ago Owen observed two History of Tolerance types of non-identical twin cattle, those that had shared a hemopoietic system in utero were tolerant of blood cells from each other and those who had not, were not cross-tolerant. 7
  8. 8. History History • Burnet postulated that there was a temporal window of tolerance such that antigens encountered while the immune system was immature tolerized the relevant lymphocytes. • Medewar subsequently investigated the effects of transferring hemopoietic cells from histoincompatible mice at different times after birth. He found that if the cells were transferred in the first few days of life (but not later) the recipient mouse acquired lifelong tolerance to the antigens of the donor. History History The Danger Hypothesis • Matzinger versus Medewar? • Polly has further suggested that the controlled death process of apoptosis is critical in • Matzinger has proposed that there is not a preventing autoimmunity when old or surplus special window for tolerance during cells are disposed. neonatal life but that whether encounter • The notion that the normal, default pathway of with an antigen results in tolerance or an the immune system is tolerance rather than immune response is determined by response is not a new idea to immunologists - whether the prevailing host environment antigens usually fail to elicit a response unless given with adjuvants, whose purpose is probably promotes a response via nonspecific cues to generate stimulatory cues (cytokines). 'sensing' danger. History History • Polly has further suggested that the controlled • Recent experiments have shown that not death process of apoptosis is critical in only can adults be tolerize under certain preventing autoimmunity when old or surplus circumstances, but that neonates can cells are disposed. make effective immune responses if the • The notion that the normal, default pathway of antigen is presented in sufficiently the immune system is tolerance rather than response is not a new idea to immunologists - immunogenic form. antigens usually fail to elicit a response unless given with adjuvants, whose purpose is probably to generate stimulatory cues (cytokines). 8
  9. 9. History • I believe that the supposed conflict between Matzinger and Medewar is rather 'hyped up' and essentially a matter of detail. • Neonatal T cells are not intrinsically tolerizable but the systemic neonatal environment does predispose to tolerance. • Nevertheless, I think that her hypothesis has drawn the attention of a wider audience to current ideas about tolerance induction and the factors determining immune responsiveness. 9

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