Selection and fine-tuning of the autoimmune T-cell repertoire (original) (raw)
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Role of thymic cortex-specific self-peptides in positive selection of T cells
Seminars in Immunology, 2010
During T cell development in the thymus, a virgin repertoire of diverse TCR␣ recognition specificities in immature thymocytes is selected through positive and negative selection to form an immunocompetent and self-tolerant repertoire of mature T cells. Positive selection supports the survival of thymocytes that receive weak signals of low-avidity TCR engagement, whereas negative selection deletes potentially harmful self-reactive thymocytes upon high-avidity TCR engagement. Early studies have highlighted the role of TCR interaction with polymorphic MHC determinants in positive selection, while negative selection imposes TCR specificity to peptide antigens displayed by MHC molecules. However, recent advances in the biology of thymic stromal cells have indicated that the formation of an immunocompetent TCR repertoire requires positive selection by thymic cortical epithelial cells expressing a unique protein degradation machinery, suggesting the role of self-peptide repertoire specifically expressed by thymic cortical epithelial cells in the development of the acquired immune system.
The Role of the Thymus in the Control of Autoimmunity
Journal of Autoimmunity, 1996
Self tolerance among T cells is believed to be maintained by two principal mechanisms: clonal deletion for self antigens expressed in the thymus and T cell anergy or T cell indifference for those whose expression is solely extrathymic. These mechanisms are passive in that they depend on autoreactive T cells being either eliminated during their maturation or rendered intrinsically non-responsive after they have matured. The data presented in this paper indicate that this scheme requires modification. First, it is evident that self antigens that are commonly regarded as being tissue-specific may also be expressed in the thymus where they influence the developing T cell repertoire.
Immunity, 1999
tive transfer experiments with CD8 ϩ cells from MHC class I (H2-D b )-reactive HY TCR transgenic mice showed that CD8 ϩ cells survived well in H2-D bϩ hosts but disappeared rapidly in H2-D bϪ mice. The above findings imply that survival of mature naive CD4 ϩ and CD8 ϩ T cells requires continuous, albeit covert, signaling through the TCR. In support of this idea, Summary T cells deficient in a Kruppel-like zinc finger transcription factor designated lung Kruppel-like factor (LKLF) were Positive selection to self-MHC/peptide complexes has found to have a very short life span (Kuo et al., 1997). long been viewed as a device for skewing the T cell Interestingly, LKLF Ϫ embryonic stem cells led to normal repertoire toward recognition of foreign peptides pre-T cell development in the thymus but to the appearance sented by self-MHC molecules. Here, we provide eviof only a few mature T cells in the periphery, because dence for an alternative possibility, namely, that the the T cells underwent spontaneous activation and died self-peptides controlling positive selection in the thyrapidly from Fas-mediated apoptosis. LKLF thus apmus serve to maintain the longevity of mature T cells pears to be involved in translating the low-level TCR in the periphery. Surprisingly, when total T cell numsignaling received from contact with self-MHC molebers are reduced, these self-ligands become overtly cules into signals for mature T cells to persist in the stimulatory and cause naive T cells to proliferate and quiescent state. undergo homeostatic expansion.
Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans
Journal of Experimental Medicine, 2002
The low frequency of self-peptide-specific T cells in the human preimmune repertoire has so far precluded their direct evaluation. Here, we report an unexpected high frequency of T cells specific for the self-antigen Melan-A/MART-1 in CD8 single-positive thymocytes from human histocompatibility leukocyte antigen-A2 healthy individuals, which is maintained in the peripheral blood of newborns and adults. Postthymic replicative history of Melan-A/MART-1specific CD8 T cells was independently assessed by quantifying T cell receptor excision circles and telomere length ex vivo. We provide direct evidence that the large T cell pool specific for the self-antigen Melan-A/MART-1 is mostly generated by thymic output of a high number of precursors. This represents the only known naive self-peptide-specific T cell repertoire directly accessible in humans.
Central Self - Tolerance by Thymic Presentation of Self - Antigens and Autoimmunity
Current Medicinal Chemistry-Immunology, Endocrine & Metabolic Agents, 2001
Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves inactivating mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T cells. During ontogeny, T cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes at the molecular level the dual role of the thymus in T cell negative and positive selection. Thymic precursors not only constitute a source of growth peptides for cryptocrine signaling between thymic stromal cells and pre-T cells, but are also processed in a way that leads to the presentation of self-antigens by thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases.
Immunity, 2012
The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA 323-339) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad 1,000−foldrange.Interestingly,higherTCRaffinitywasassociatedwithalargerTregcelldevelopmental′′niche′′size,eventhoughtheamountofantigenshouldremainconstant.TheTCR−reactivitythresholdtoelicitthymicnegativeselectionandperipheralTcellresponseswas1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental ''niche'' size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was 1,000−foldrange.Interestingly,higherTCRaffinitywasassociatedwithalargerTregcelldevelopmental′′niche′′size,eventhoughtheamountofantigenshouldremainconstant.TheTCR−reactivitythresholdtoelicitthymicnegativeselectionandperipheralTcellresponseswas100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.
F1000 - Post-publication peer review of the biomedical literature, 2012
Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8 + T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.