The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells
The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells
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DOI：
10.1073/pnas.1309378110
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发表时间：
2013-09-10
影响因子：
11.1
通讯作者：
Huber, Magdalena
中科院分区：
文献类型：
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作者：
Raczkowski, Friederike;Ritter, Josephine;Huber, Magdalena
强大的细胞毒性CD8(+) t细胞应答对于细胞内病原体的免疫是重要的。在这里，我们发现转录因子IFN调节因子4 （IRF4）对于细胞内单核增生李斯特菌的保护性CD8(+) t细胞应答至关重要。Irf4缺陷（Irf4(-/-)）小鼠不能清除单核增生乳杆菌感染，产生的单核增生乳杆菌特异性CD8(+) T细胞数量减少，效应表型和功能受损。将野生型CD8(+) T细胞转移到Irf4（-/-）小鼠体内，可提高细菌清除率，提示Irf4（-/-）小鼠体内CD8+ T细胞存在内在缺陷。在转移到野生型受体后，Irf4(-/-) CD8(+) T细胞在单核增生乳杆菌感染后被激活并表现出初始增殖。然而，这些细胞不能维持增殖，产生少量的ifn - γ和tnf - α，并且不能获得细胞毒性功能。在IRF4 (-/-) CD8(+) T细胞中强制表达IRF4挽救了这一缺陷。在急性感染期间，Irf4(-/-) CD8(+) T细胞表现出B淋巴细胞诱导成熟蛋白1 （Blimp-1）、DNA结合抑制剂（Id） 2和T细胞中表达的T-box （T-bet）的表达减少，转录因子编程效应细胞生成。IRF4对Blimp-1的表达至关重要，提示Blimp-1调控的改变导致了IRF4 (-/-) CD8(+) T细胞的缺陷。尽管b细胞淋巴瘤6 （BCL-6）、Eomesodermin和Id3水平升高，但Irf4(-/-) CD8(+) T细胞显示记忆细胞形成受损，表明Irf4在这一过程中具有额外的功能。由于IRF4调控b细胞和CD4(+) t细胞分化，其在外周血CD8(+) t细胞分化中起决定性作用的鉴定表明，IRF4在适应性淋巴细胞命运决定中具有共同的调节功能。
Robust cytotoxic CD8(+) T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8(+) T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4(-/-)) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenes-specific CD8(+) T cells with impaired effector phenotype and function. Transfer of wild-type CD8(+) T cells into Irf4(-/-) mice improved bacterial clearance, suggesting an intrinsic defect of CD8+ T cells in Irf4(-/-) mice. Following transfer into wild-type recipients, Irf4(-/-) CD8(+) T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-gamma and TNF-alpha, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4(-/-) CD8(+) T cells rescued the defect. During acute infection, Irf4(-/-) CD8(+) T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id) 2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4(-/-) CD8(+) T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4(-/-) CD8(+) T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4(+) T-cell differentiation, the identification of its decisive role in peripheral CD8(+) T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.