Zehn Dietmar, Bevan Michael J
Department of Immunology, Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Immunity. 2006 Aug;25(2):261-70. doi: 10.1016/j.immuni.2006.06.009. Epub 2006 Aug 3.
T cells causing autoimmunity must escape tolerance. We observed that CD8(+) T cells with high avidity for an antigen expressed in the pancreas, kidney, and thymic medulla were efficiently removed from a polyclonal repertoire by central and peripheral tolerance mechanisms. However, both mechanisms spared low-avidity T cells from elimination. Neither the introduction of activated, self-antigen-specific CD4(+) helper T cells nor a global inflammatory stimulus were sufficient to activate the low-avidity CD8(+) T cells and did not break tolerance. In contrast, challenge with a recombinant bacterium expressing the self antigen primed the low-avidity T cells, and the animals rapidly developed autoimmune diabetes. We suggest that whereas thymic and peripheral tolerance mechanisms remove cells that can be primed by endogenous amounts of self antigen, they do not guard against tissue destruction by low-avidity effector T cells, which have been primed by higher amounts of self antigen or by crossreactive antigens.
引发自身免疫的T细胞必须逃避免疫耐受。我们观察到，对胰腺、肾脏和胸腺髓质中表达的抗原具有高亲和力的CD8(+) T细胞通过中枢和外周耐受机制从多克隆库中被有效清除。然而，这两种机制都使低亲和力T细胞免于被清除。无论是引入活化的、自身抗原特异性的CD4(+)辅助性T细胞，还是全身性炎症刺激，都不足以激活低亲和力CD8(+) T细胞，也无法打破免疫耐受。相反，用表达自身抗原的重组细菌进行攻击可使低亲和力T细胞致敏，动物会迅速发展为自身免疫性糖尿病。我们认为，虽然胸腺和外周耐受机制会清除那些可被内源性自身抗原激活的细胞，但它们无法防止低亲和力效应T细胞对组织的破坏，这些低亲和力效应T细胞已被大量自身抗原或交叉反应性抗原激活。
