TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation
TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation
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DOI：
10.1073/pnas.1205742109
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发表时间：
2012-10-09
影响因子：
11.1
通讯作者：
Berg, Leslie J.
中科院分区：
文献类型：
--
作者：
Nayar, Ribhu;Enos, Megan;Berg, Leslie J.
胸腺中的CD 8（+）T细胞发育产生主要群体的常规幼稚细胞，沿着少数群体的类似记忆细胞的“先天”T细胞。最近的研究分析了各种KO或基因敲入小鼠，表明T细胞受体（TCR）信号通路的损伤产生了先天性CD 8（+）T细胞数量的增加，其特征是CD 44、CD 122、CXCR 3和转录因子Eomesodermin（Eomes）的高表达。这种改变的发展的一个组成部分是IL-4的非CD 8（+）T细胞内在作用。为了确定CD 8（+）T细胞内减少的TCR信号传导是否也可能有助于这一途径，我们研究了转录因子IFN调节因子4（IRF 4）的作用。IRF 4在WT T细胞中TCR刺激后上调;此外，这种上调在用Tec家族酪氨酸激酶的小分子抑制剂IL-2诱导型T细胞激酶（ITK）处理的T细胞中受损。与WT细胞相反，IRF 4缺陷型CD 8（+）T细胞的活化导致Eomes的快速和稳健表达，其通过IL-4刺激进一步增强。此外，ITK与IL-4一起抑制增加Eomeso上调。这些数据表明，ITK信号转导促进了CD 8（+）T细胞活化后IRF 4的上调，并且该信号转导途径通常抑制Eomes表达，从而调节CD 8（+）T细胞的分化途径。
CD8(+) T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of "innate" T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8(+) T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8(+) T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8(+) T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8(+) T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8(+) T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8(+) T cells.