Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity
Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity
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DOI：
10.1053/j.gastro.2008.01.070
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发表时间：
2008-04-01
期刊：
影响因子：
29.4
通讯作者：
Khazaie, Khashayarsha
中科院分区：
文献类型：
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作者：
Magnusson, Fay C.;Liblau, Roland S.;Khazaie, Khashayarsha
背景与目的：肠胶质细胞（EGC）网络的破坏是克罗恩病的早期病理特征。为了确定抗原特异性CD8和CD4 T细胞对EGC网络破坏的贡献，我们研究了EGC表达的异位抗原的特异性自身免疫靶向。方法：在EGCs中表达流感血凝素（HA）的转基因小鼠（GFAP-HA），要么与对HA的主要组织相容性复合体（MHC） I类表位（CL4-TCR）特异性T细胞受体（TCR）转基因小鼠杂交，要么与传统的CL4 T细胞过继转移。将这些小鼠与用MHC II类HA表位特异性的常规T细胞转移的gmap -HA小鼠（6.5）进行比较。结果：CD8和CD4 t细胞亚型在体内均以抗原特异性方式被激活；然而，它们在肠系膜淋巴结扩张、触发促炎细胞因子和诱导肠道自身免疫损伤的能力上存在很大差异。直接呈递抗原，由淋巴结基质提供。引起CD8 T细胞的激活和缺失。这种T细胞耐受机制不影响CD4 T细胞，CD4 T细胞产生抗原特异性致死自身免疫。结论：我们的观察结果支持最近确定的外周T细胞耐受机制，该机制特异性地保护免受传统CD8 T细胞介导的自身免疫。此外，我们发现传统的CD4 T细胞不受这种耐受机制的影响，它们靶向EGCs产生致命的肠道自身免疫。
Background & Aims: Disruption of the enteric glial cell (EGC) network is an early pathologic feature in Crohn's disease. To determine the contribution of antigen-specific CD8 and CD4 T cells to the breakdown of the EGC network, we studied specific autoimmune targeting of an ectopic antigen expressed by EGCs. Methods: Transgenic mice (GFAP-HA), which express the influenza hemagglutinin (HA) in EGCs, were either crossed with mice transgenic for a T-cell receptor (TCR) specific for a major histocompatibility complex (MHC) class I epitope of HA (CL4-TCR) or were adoptively transferred with conventional CL4 T cells. These were compared with GFAP-HA mice transferred with conventional T cells specific for an MHC class II epitope of HA (6.5). Results: Both CD8 and CD4 T-cell subtypes were activated in vivo in an antigen-specific manner; however, they differed substantially in their ability to expand in the mesenteric lymph nodes, trigger proinflammatory cytokines, and induce autoimmune damage in the intestine. Direct presentation of antigen, provided by lymph node stromal. cells, caused the activation and deletion of CD8 T cells. This mechanism of T-cell tolerance did not affect CD4 T cells, which produced antigen-specific lethal autoimmunity. Conclusions: Our observations support a recently identified mechanism of peripheral T-cell tolerance that specifically protects against autoimmunity mediated by conventional CD8 T cells. Furthermore, we show that conventional CD4 T cells are not affected by this mechanism of tolerance, and their targeting of EGCs produces lethal intestinal autoimmunity.