Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation.
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.
Chen
Weiling
W
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Zhang
Linging
L
Liang
Bitao
B
Saenger
Yvonne
Y
Li
Jianfeng
J
Chess
Leonard
L
Jiang
Hong
H
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018834:Chaperonin 60 / Q000032:analysis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000032:analysis / Q000276:immunology; D014611:Vaccination
D018834:Chaperonin 60; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C032907:Q surface antigens; C090580:Qdm protein, mouse