The specificity of T cell regulation that enables self-nonself discrimination in the periphery

Abstract

It was recently shown that perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to control autoimmune disease. This regulation is achieved by CD8 ؉ T cells that recognize a common surrogate target structure, Qa-1/Hsp60sp, preferentially expressed by activated T cells of intermediate but not high avidity. A truncated self-reactive repertoire, devoid of high-avidity T cells, generated by thymic negative selection, allows selective downregulation of intermediate-avidity T cells to accomplish self-nonself discrimination in the periphery. Identification of the common surrogate target structure expressed on intermediate-avidity T cells opens up a conceptual theme to understand the relationship between the specificity of peripheral immune regulation and self-nonself discrimination. Here, we investigated peptide vaccination induced crossprotection mediated by CD8 ؉ T cells in two autoimmune disease models, experimental allergic encephalomyelitis (EAE) and type 1 diabetes (T1D). We show that Qa-1 restricted CD8 ؉ T cells crossprotect animals from either EAE or T1D without abrogating the immune response to foreign antigens. Cross-protection occurs because potentially pathogenic self-reactive T cells included in the pool of intermediate-avidity T cells are capable of preferentially expressing common surrogate target structures on their surface to render themselves subject to the down-regulation, independent of the specificity of the antigens that they are triggered by. Thus, like in the thymus, the immune system discriminates self from nonself, during adaptive immunity in the periphery, not by recognizing the structural differences between self and foreign antigens, but rather by perceiving the avidity of T cell activation.avidity model ͉ Qa-1/HLA-E-restricted CD8 ϩ T cells ͉ Qa-1/Hsp60sp ͉ autoimmune disease ͉ cross-protection

HLA-E–restricted regulatory CD8+ T cells are involved in development and control of human autoimmune type 1 diabetes

“…However, while releasing the "innocent" selfreactive T cells with low avidity, thymic negative selection also allows a large fraction of self-reactive T cells of intermediate avidity to be released into the periphery under normal circumstances (10)(11)(12), and functional activation of this population of cells has the potential to elicit pathogenic autoimmunity (12)(13)(14)(15). The potential to develop autoimmune disease is therefore inherent in every individual and must be specifically dealt with by peripheral regulatory mechanisms (6)(7)(8)(9). In this regard, we have demonstrated in murine studies that self/nonself discrimination is accomplished by thymic negative selection followed by peripheral T cell regulation in which Qa-1-restricted CD8 + T cells selectively downregulate intermediateavidity T cells activated by any antigens (6)(7)(8).…”

“…We have previously proposed and tested an "avidity model" of peripheral T cell regulation that postulates that, like in the thymus, the immune system discriminates self from nonself during adaptive immunity in the periphery not by recognizing the structural differences between self versus foreign antigens, but rather by perceiving the avidity of T cell activation (6)(7)(8)(9). It is generally accepted that thymic negative selection, in which, high-avidity self-reactive thymocytes are deleted, eliminates the imminent danger of pathogenic autoimmunity in the periphery and is the major mechanism of central self-tolerance (3)(4)(5).…”

“…The potential to develop autoimmune disease is therefore inherent in every individual and must be specifically dealt with by peripheral regulatory mechanisms (6)(7)(8)(9). In this regard, we have demonstrated in murine studies that self/nonself discrimination is accomplished by thymic negative selection followed by peripheral T cell regulation in which Qa-1-restricted CD8 + T cells selectively downregulate intermediateavidity T cells activated by any antigens (6)(7)(8). Since the peripheral self-reactive T cell repertoire is devoid of high-avidity self-reactive cells due to thymic negative selection, the selective downregulation of intermediate-avidity T cells simultaneously enables the suppression of autoimmunity and the preservation of the functional antiinfection immunity, which is dominated by high-avidity T cells.…”

Glatiramer acetate ameliorates inflammatory bowel disease in mice through the induction of Qa‐1‐restricted CD8+ regulatory cells

“…Qa-1-restricted CD8 + Treg cells can be induced by both T-cell vaccination (TCV) [16] and activation of CD4 + T cells upon peptide immunization [17]. Since activation of enteroantigen-specific CD4 + T cells is also playing crucial roles in the pathogenesis of IBD, we were interested in evaluating the therapeutic effects of Qa-1-restricted CD8 + T cells on experimental IBD and exploring potential therapeutic approaches toward this disease through the induction of CD8 + suppressor cells.…”

CD8+ Regulatory T Cells Induced by T Cell Vaccination Protect Against Autoimmune Nephritis

“…6 CD8+ Tregs specific for Qa-1-expressing, intermediateaffinity CD4 effector T cells have been found in EAE and type 1 diabetes models induced by vaccination with antigen but targeted at T cells with intermediate avidity distinct from antigen specificity in keeping with a nonantigen-driven mechanism of suppression. 14 In humans, increased expression of HLA-E is found on effector cells in multiple sclerosis. Mice can be protected from EAE by TCV.…”