Targeting Antigen to Diverse APCs Inactivates Memory CD8+ T Cells without Eliciting Tissue-Destructive Effector Function
Targeting Antigen to Diverse APCs Inactivates Memory CD8+ T Cells without Eliciting Tissue-Destructive Effector Function
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DOI：
10.4049/jimmunol.0900032
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发表时间：
2010-01-15
影响因子：
4.4
通讯作者：
Steptoe, Raymond J.
中科院分区：
文献类型：
--
作者：
Kenna, Tony J.;Waldie, Tanya;Steptoe, Raymond J.
记忆T细胞在自身免疫性疾病的临床前阶段早期发育，传统上被认为对耐受诱导具有抗性。因此，它们可能是成功免疫治疗已建立的自身免疫性疾病的有效障碍。最近的研究表明，当抗原基因靶向稳态树突状细胞时，记忆性CD 8（+）T细胞反应就会终止。然而，在这些条件下，记忆性CD 8（+）T细胞的失活是缓慢的，允许短暂扩增的记忆性CD 8（+）T细胞发挥组织破坏性效应子功能。在这项研究中，我们比较了不同的Ag靶向策略，并显示，使用MHC II类启动子驱动不同范围的APC中的Ag表达，CD 8（+）记忆T细胞可以通过涉及TCR的快速和持续下调的机制被MHC II类造血APC快速灭活，其中CD 8（+）记忆细胞的效应子应答被迅速截短，并防止表达Ag的靶组织破坏。我们的数据首次证明，将Ag基因靶向广泛的MHC II类+ APC类型是终止记忆性CD 8（+）T细胞应答的高效方法，以防止组织破坏性效应子功能和潜在的自身免疫性疾病。免疫学杂志，2010，184：598-606。
Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8(+) T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8(+) T cells is slow, allowing transiently expanded memory CD8(+) T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8(+) memory T cells can be rapidly inactivated by MHC class II hematopoietic APCs through a mechanism that involves a rapid and sustained down-regulation of TCR, in which the effector response of CD8(+) memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8(+) T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. The Journal of Immunology, 2010, 184: 598-606.