TY - JOUR
T1 - Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation
AU - Chen, Weiling
AU - Zhang, Linging
AU - Liang, Bitao
AU - Saenger, Yvonne
AU - Li, Jianfeng
AU - Chess, Leonard
AU - Jiang, Hong
PY - 2007/12/18
Y1 - 2007/12/18
N2 - The structure recognized by regulatory T cells that enables them to discriminate self from nonself in the periphery is one of the central issues of regulatory T cell biology. A link between immunoregulation and self-nonself discrimination has emerged from experiments showing that Qa-1-restricted CD8+ T cells selectively down-regulate target T cells activated by the intermediate avidity of their own T cell antigen receptor-ligand interactions. Because the peripheral self-reactive T cell repertoire is devoid of high-avidity T cells compared with the foreign-reactive repertoire, as a result of thymic negative selection, the selective down-regulation of intermediate but not high-avidity T cells enables the immune system to suppress autoimmunity without damaging the ongoing immune response to foreign pathogens. However, the molecular mechanism delineating how avidity of T cell activation is perceived by the regulatory T cells has not been elucidated. Here we show that a heat shock peptide (Hsp60sp), coupled with the MHC class Ib molecule Qa-1, is a surrogate target structure that is preferentially expressed at a higher level on the intermediate avidity T cells and specifically recognized by the Qa-1-restricted CD8+ T cells. The biological significance of this observation was confirmed by the ability of Hsp60sp-loaded relevant dendritic cells to induce a Qa-1-restricted CD8+ T cell-mediated protection from autoimmune encephalopathy in the experimental allergic encephalomyelitis model. Thus, perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to discriminate self from nonself in the periphery to maintain self-tolerance.
AB - The structure recognized by regulatory T cells that enables them to discriminate self from nonself in the periphery is one of the central issues of regulatory T cell biology. A link between immunoregulation and self-nonself discrimination has emerged from experiments showing that Qa-1-restricted CD8+ T cells selectively down-regulate target T cells activated by the intermediate avidity of their own T cell antigen receptor-ligand interactions. Because the peripheral self-reactive T cell repertoire is devoid of high-avidity T cells compared with the foreign-reactive repertoire, as a result of thymic negative selection, the selective down-regulation of intermediate but not high-avidity T cells enables the immune system to suppress autoimmunity without damaging the ongoing immune response to foreign pathogens. However, the molecular mechanism delineating how avidity of T cell activation is perceived by the regulatory T cells has not been elucidated. Here we show that a heat shock peptide (Hsp60sp), coupled with the MHC class Ib molecule Qa-1, is a surrogate target structure that is preferentially expressed at a higher level on the intermediate avidity T cells and specifically recognized by the Qa-1-restricted CD8+ T cells. The biological significance of this observation was confirmed by the ability of Hsp60sp-loaded relevant dendritic cells to induce a Qa-1-restricted CD8+ T cell-mediated protection from autoimmune encephalopathy in the experimental allergic encephalomyelitis model. Thus, perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to discriminate self from nonself in the periphery to maintain self-tolerance.
KW - Autoimmune diseases
KW - Qa-1/HLA-E-restricted regulatory CD8 T cells
KW - Self-nonself discrimination
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U2 - 10.1073/pnas.0709878104
DO - 10.1073/pnas.0709878104
M3 - Article
C2 - 18077361
AN - SCOPUS:38049172962
SN - 0027-8424
VL - 104
SP - 20472
EP - 20477
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -