B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.
B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.
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DOI：
10.4049/jimmunol.1201241
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发表时间：
2012-10-15
期刊：
影响因子：
--
通讯作者：
Zang X
中科院分区：
文献类型：
--
作者：
Lee JS;Scandiuzzi L;Ray A;Wei J;Hofmeyer KA;Abadi YM;Loke P;Lin J;Yuan J;Serreze DV;Allison JP;Zang X
B7 x（B7-H4或B7 S1）是B7家族的第七个成员，其体内功能仍不清楚。尽管新的遗传数据将B7 x基因与自身免疫性疾病联系起来，但它究竟如何促进外周耐受和自身免疫尚不清楚。在这里，我们发现在人类和小鼠的抗原递呈细胞或T细胞上都没有检测到B7 x蛋白，这在B7家族中是独一无二的。由于B7 x蛋白在一些外周细胞如胰腺β细胞中表达，我们利用CD 8 T细胞介导的糖尿病模型（AI 4 αβ），其中CD 8 T细胞识别内源性自身抗原，并且发现缺乏B7 x的小鼠比对照AI 4 αβ小鼠发展更严重的糖尿病。相反，在β细胞中过表达B7 x的小鼠（Rip-B7 xAI 4 αβ）无糖尿病。此外，效应子AI 4 αβ CD 8 T细胞的过继转移在对照小鼠中诱导糖尿病，但在Rip-B7 xAI 4 αβ小鼠中不诱导。机制研究表明，致病性效应CD 8 T细胞能够迁移到胰腺，但在Rip-B7 xAI 4 αβ小鼠中遇到局部B7 x时未能稳健地破坏组织。尽管Rip-B7 xAI 4 αβ小鼠和AI 4 αβ小鼠中的AI 4 αβ CD 8 T细胞显示出相似的细胞毒性功能、细胞死亡和整体基因表达谱，但这些细胞在AI 4 αβ小鼠中比在RIP-B7 xAI 4 αβ小鼠中具有更大的增殖。这些结果表明，非淋巴器官中的B7 x部分通过抑制组织特异性CD 8 T细胞的增殖来防止外周自身免疫，并且胰腺β细胞上的B7 x局部过表达足以消除CD 8 T细胞诱导的糖尿病。
B7x (B7-H4 or B7S1) is the seventh member of the B7 family and the in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. Here we showed that B7x protein was not detected on antigen-presenting cells or T cells in both human and mice, which is unique in the B7 family. As B7x protein is expressed in some peripheral cells such as pancreatic β cells, we utilized a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-antigen, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ mice and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.
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DOI：
10.1084/jem.180.2.631
发表时间：
1994-08-01
期刊：
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影响因子：
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作者：
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