Tissue-Resident Exhausted Effector Memory CD8+ T Cells Accumulate in the Retina during Chronic Experimental Autoimmune Uveoretinitis
Tissue-Resident Exhausted Effector Memory CD8+ T Cells Accumulate in the Retina during Chronic Experimental Autoimmune Uveoretinitis
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DOI：
10.4049/jimmunol.1301390
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发表时间：
2014-05-15
影响因子：
4.4
通讯作者：
Nicholson, Lindsay B.
中科院分区：
文献类型：
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作者：
Boldison, Joanne;Chu, Colin J.;Nicholson, Lindsay B.
实验性自身免疫性葡萄膜视网膜炎是人类非感染性眼内后段炎症的模型。虽然这种疾病是CD4（+）T细胞依赖性的，但在疾病的持续阶段，CD8（+）T细胞积聚。我们发现，这些是效应记忆CD8（+）T细胞，不同于它们的脾脏对应物的表面表达的CD69，CD103，和Ly6C。这些视网膜效应记忆CD8（+）T细胞具有有限的细胞毒性效应功能，其响应Ag特异性刺激的增殖能力受损，并上调程序性死亡1受体。在疾病晚期用芬戈莫德（FTY 720）治疗显示视网膜CD8（+）T细胞是组织驻留的。尽管有衰竭的迹象，但这些细胞是功能性的，因为它们的耗竭导致视网膜CD4（+）T细胞和CD11b（+）巨噬细胞的扩增。这些结果表明，在慢性自身免疫性炎症期间，耗尽的CD8+ T细胞在局部组织中建立。它们在表型上不同于外周CD8（+）T细胞，并通过表达抑制性受体（如程序性死亡1）在组织内提供局部信号，从而限制持续性炎症。
Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4(+) T cell dependent, in the persistent phase of disease CD8(+) T cells accumulate. We show that these are effector memory CD8(+) T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8(+) T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8(+) T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4(+) T cells and CD11b(+) macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8+ T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8(+) T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation.