CD95 (FAS) DEPENDENT ELIMINATION OF SELF-REACTIVE B-CELLS UPON INTERACTION WITH CD4(+) T-CELLS
CD95 (FAS) DEPENDENT ELIMINATION OF SELF-REACTIVE B-CELLS UPON INTERACTION WITH CD4(+) T-CELLS
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DOI：
10.1038/376181a0
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发表时间：
1995-07-13
期刊：
影响因子：
64.8
通讯作者：
GOODNOW, CC
中科院分区：
文献类型：
--
作者：
RATHMELL, JC;COOKE, MP;GOODNOW, CC
隐性小鼠突变lpr和gld分别在相互作用的一对细胞表面分子CD 95（Fas/APO-1）和Fas配体（FasL）中产生缺陷（1-3），导致类似于人类系统性红斑狼疮的自身抗体产生（4）。受两种分子缺陷影响的自身耐受机制尚未确定，但识别主要组织相容性复合体（MHC）II类分子的B细胞和CD 4（+）T细胞中的CD 95缺陷是lpr小鼠自身免疫所需的（5-8）。在这里，我们跟踪体内的结果之间的相互作用B细胞和CD 4（+）T细胞，识别转基因编码的自身抗原，鸡蛋溶菌酶（HEL），使用细胞从小鼠转基因免疫球蛋白和T细胞受体（TCR）基因。先前未遇到HEL自身抗原的B细胞（初始细胞）在与抗原和HEL特异性CD 4（+）T细胞相互作用后被触发增殖和抗体产生。相比之下，在发育过程中长期暴露于HEL并携带脱敏表面免疫球蛋白（sIg）抗原受体（9）的B细胞（无反应性细胞）不产生抗体，而是在存在HEL特异性CD 4（+）T细胞的情况下被消除。然而，缺乏CD 95的无反应性B细胞不能被CD 4（+）T细胞清除，并被触发增殖。这些发现确定了一个新的调节步骤，消除自身反应性B细胞，似乎独特的依赖于CD 95。
THE recessive mouse mutations lpr and gld create deficiencies in an interacting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-ligand (FasL), respectively(1-3), resulting in autoantibody production resembling human systemic lupus erythematosus(4). The mechanisms of self-tolerance affected by deficiency in either molecule are not established, but CD95 deficiency both in B cells and in CD4(+) T cells recognizing major histocompatibility complex (MHC) class II molecules is required for autoimmunity in lpr mice(5-8). Here we track the outcome of in vivo interactions between B cells and CD4(+) T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells from mice transgenic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive cells) were triggered into proliferation and antibody-production upon interaction with antigen and HEL-specific CD4(+) T cells. By contrast, B cells that had been chronically exposed to HEL during their development and carried desensitized surface immunoglobulin (sIg) antigen receptors(9) (anergic cells) did not produce antibody but instead were eliminated in the presence of HEL-specific CD4(+) T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4(+) T cells and were triggered to proliferate. These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95.