Cellular FLICE-inhibitory protein is required for T cell survival and cycling
Cellular FLICE-inhibitory protein is required for T cell survival and cycling
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DOI：
10.1084/jem.20050118
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发表时间：
2005-08-01
影响因子：
15.3
通讯作者：
Yeh, WC
中科院分区：
文献类型：
--
作者：
Chau, H;Wong, V;Yeh, WC
Fas相关死亡结构域（FADD）和caspase-8是死亡受体诱导的细胞凋亡的关键信号转导子，而细胞FLICE抑制蛋白（cFLIP）拮抗这一过程。有趣的是，FADD和胱天蛋白酶-8也在T细胞发育和T细胞受体（TCR）介导的增殖反应中发挥作用。为了研究潜在的机制，我们通过用cFLIP缺陷的胚胎干细胞重建Rag（-/-）囊胚来产生cFLIP缺陷的T细胞。这些Rag嵌合突变小鼠（rcFLIP（-/-））的胸腺、淋巴结和脾脏中的T细胞数量严重减少，尽管成熟T淋巴细胞确实发育。类似于FADD-或半胱天冬酶-8-缺陷细胞，rcFLIP（-/-）T细胞响应于TCR刺激而增殖受损。进一步的研究表明，cFLIP是T细胞存活以及响应TCR刺激的T细胞循环所必需的。有趣的是，来自TCR复合物的一些信号传导途径似乎是有效的，因为CD 3加CD 28交联能够激活rcFLIP（-/-）T细胞中的ERK途径。我们证明了cFLIP在T细胞功能中的重要作用。
Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)-mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag(-/-) blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP(-/-)) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8-deficient cells, rcFLIP(-/-) T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP(-/-) T cells. We demonstrate an essential role for cFLIP in T cell function.