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The T cell repertoire primed by antiviral vaccination is influenced by self-tolerance.
Vaccination can elicit CD8(+) cytotoxic T lymphocytes (CTL) that recognize peptides presented by class I MHC molecules. Relatively little is known, however, about the genetic factors that shape the repertoire of T cell clonotypes responding to any given epitope. We report here that H-2(b) mice immunized with a plasmid DNA vaccine or vaccinia virus encoding for HIV-1SF2p55gag elicit CD8(+) CTL against the H-2Db-restricted immunodominant epitope (pgagb). This response involved three different T cell populations based on their recognition of alloantigens: one that cross-reacted with the alloantigen H-2Ld, one that cross-reacted with H-2Kd, and one that did not cross-react with either H-2(d) or H-2(k) molecules. Using the TAP-deficient cell line T2-Ld, we showed that pgagb-specific CTL cross-react with H-2Ld and a yet unidentified self-peptide. In mice expressing H-2(b) and H-2(d) allotypes, we investigated whether tolerance to H-2(d) influenced the HIVp55gag-specific CTL repertoire as a consequence of thymic deletion of the cross-reactive CTL repertoire. In (H-2(dxb))F1 mice heterogygosity at the MHC-I level prevented maturation of some but not all TCR combinations specific for H-2Db+pgagb, illustrating the concept that self-tolerance can influence the repertoire of antiviral T cells.
Nihility: discovery of the immunologic zero corner where self-tolerance and clonal deletion are challenged.
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Self-tolerance alters T-cell receptor expression in an antigen-specific MHC restricted immune response.
The influence of major histocompatibility complex (MHC) gene products on the T-lymphocyte alpha beta receptor (TCR) repertoire is well documented, but how specificity is also generated for a diverse array of foreign peptide antigens is unknown. One proposed mechanism is that the TCR repertoire is selected by the recognition of processed self-antigens bound to MHC molecules. Here, we examine the influence of non-MHC-encoded self-antigens on the TCR repertoire expressed in an antigen-specific immune response. Most pigeon cytochrome c-specific, Ek alpha Ek beta (Ek) Ia-restricted T cells from B10.A mice express a product of the V alpha 11 gene family in association with a V beta 3 gene-encoded protein. We therefore examined V alpha 11 and V beta 3 gene expression in cytochrome c-specific T-cell lines derived from various mouse strains with different non-MHC genetic backgrounds. T cells from several strains failed to express any V beta 3 due to tolerance induced by Mlsc-encoded self-antigens. Variable levels of V alpha 11 messenger RNA (mRNA) were expressed by antigen-specific T cells from all the strains. In one strain V beta 3 was expressed in the relative absence of V alpha 11. These results directly demonstrate that self-tolerance alters TCR gene usage in the immune response to a foreign antigen, and indicate that TCR V alpha and V beta proteins may, in part, be independently selected.
Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance.
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Induction of skin allograft tolerance during metamorphosis of the toad Xenopus laevis: a possible model for studying generation of self tolerance to histocompatibility antigens.
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The role of deletion versus regulation in the maintenance of self-tolerance.
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Receptor editing, immune diversification, and self-tolerance.
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Balancing immunity, autoimmunity, and self-tolerance.
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Mechanisms underlying the loss of self tolerance in NOD mice.
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Viral damage and the breakdown of self-tolerance.
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Critical self-epitopes are key to the understanding of self-tolerance and autoimmunity.
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Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease.
We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139-151, on the experimental autoimmune encephalomyelitis-resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell-activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.
Self tolerance of natural MHC class I ligands.
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APECED: a monogenic autoimmune disease providing new clues to self-tolerance.
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Induced tolerance in F1 rats to anti-major histocompatibility complex receptors on parental T cells. Implications for self tolerance.
The immunogenicity of cell surface markers associated with specific anti-major histocompatibility complex (MHC) alloreactivity of rat peripheral T lymphocyte subpopulations has been demonstrated in the past by the ability of such cell populations to induce a profound and specific resistance to systemic graft-vs.-host (GVH) disease in adult rats. Our studies demonstrate that these specificity-associated anti-MHC parental strain T cell markers are also tolerogenic; if small numbers of parental strain T cells are administered to newborn F1 rats, they result in the specific inability to induce GVH resistance later on in adult life. Moreover, unlike normal animals, these F1 rats are extremely sensitive to systemic GVH disease caused by T cells from the original donor parental strain.
Self-tolerance checkpoints in B lymphocyte development.
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The TGF-beta1/Foxp3 regulatory axis in immune self-tolerance: implications for health and disease.
CD4(+) regulatory T cells (T(REG)) are important contributors to the induction and maintenance of peripheral tolerance. It is now becoming evident that this heterogeneous population consists of naturally occurring and induced CD4(+) T(REG) cells that share between themselves key immunoregulatory characteristics. Their phenotype and function often relies on the expression of Foxp3 transcription factor (TF) and the presence of the immunomodulating cytokine TGF-beta1. The interdependence of TGF-beta1 and Foxp3 in the induction and maintenance of regulatory T cell networks is gradually being elucidated, shedding new light on peripheral tolerance. Thus, comprehension and delimitation of those processes predict the development of novel therapies for the treatment of infectious and autoimmune diseases, cancer and graft rejection.