CTLA-4 expressed by FOXP3+ regulatory T cells prevents inflammatory tissue attack and not T-cell priming in arthritis
CTLA-4 expressed by FOXP3+ regulatory T cells prevents inflammatory tissue attack and not T-cell priming in arthritis
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DOI：
10.1111/imm.12754
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发表时间：
2017-09-01
期刊：
影响因子：
6.4
通讯作者：
Wing, Kajsa
中科院分区：
文献类型：
--
作者：
Klocke, Katrin;Holmdahl, Rikard;Wing, Kajsa
细胞毒性T淋巴细胞抗原4（CTLA-4）介导的已经耐受的自身反应性T细胞的调节对于理解自身免疫应答至关重要。尽管CTLA-4的缺陷导致类风湿性关节炎中FOXP 3（+）调节性T（Treg）细胞功能异常，但其在自身反应性T细胞中的作用仍然难以捉摸。我们研究了对胶原诱导的关节炎中的主导II型胶原（CII）T细胞表位的免疫力，包括异源环境和CII在小鼠软骨中E266 D位置突变的自体环境。CTLA-4调节关节炎的所有阶段，包括慢性期，并影响自体而非异源CII反应性T细胞的引发。需要常规T（Tconv）细胞和Treg细胞两者的CTLA-4表达，但是虽然需要Tconv细胞表达来控制初始自身反应性T细胞的引发，但Treg细胞上的CTLA-4防止炎性组织攻击。这确定了CTLA-4介导的耐受性最强时的细胞类型特异性时间窗，这对免疫调节药物的临床治疗具有重要意义。
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) -mediated regulation of already tolerized autoreactive T cells is critical for understanding autoimmune responses. Although defects in CTLA-4 contribute to abnormal FOXP3(+) regulatory T (Treg) cell function in rheumatoid arthritis, its role in autoreactive T cells remains elusive. We studied immunity towards the dominant collagen type II (CII) T-cell epitope in collagen-induced arthritis both in the heterologous setting and in the autologous setting where CII is mutated at position E266D in mouse cartilage. CTLA-4 regulated all stages of arthritis, including the chronic phase, and affected the priming of autologous but not heterologous CII-reactive T cells. CTLA-4 expression by both conventional T (Tconv) cells and Treg cells was required but while Tconv cell expression was needed to control the priming of naive autoreactive T cells, CTLA-4 on Treg cells prevented the inflammatory tissue attack. This identifies a cell-type-specific time window when CTLA-4-mediated tolerance is most powerful, which has important implications for clinical therapy with immune modulatory drugs.