Tyk2-Dependent Bystander Activation of Conventional and Nonconventional Th1 Cell Subsets Contributes to Innate Host Defense against Listeria monocytogenes Infection
Tyk2-Dependent Bystander Activation of Conventional and Nonconventional Th1 Cell Subsets Contributes to Innate Host Defense against Listeria monocytogenes Infection
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DOI：
10.4049/jimmunol.1303067
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发表时间：
2014-05-15
影响因子：
4.4
通讯作者：
Yamada, Hisakata
中科院分区：
文献类型：
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作者：
Hashiguchi, Tomomitsu;Oyamada, Akiko;Yamada, Hisakata
IL-12 是针对单核细胞增生李斯特菌等细胞内细菌产生的，可促进病原体特异性 Th1 细胞的发育，这些细胞在宿主防御中发挥重要作用。然而，人们也知道，具有Th1功能的CD44（高）记忆表型CD4 T细胞自然存在于幼稚小鼠中，并且淋巴细胞减少诱导的幼稚CD4 T细胞增殖产生具有Th1功能的记忆表型CD4 T细胞，尽管它们的分化机制和对宿主防御的贡献尚不清楚。在这项研究中，我们使用缺乏酪氨酸激酶 2 (Tyk2) 的小鼠分析了 Th1 细胞不同亚群的发育和功能，酪氨酸激酶 2 (Tyk2) 是与 IL-12 信号传导密切相关的 Janus 激酶家族的成员。与传统 Ag 特异性 Th1 细胞的情况相反，Tyk2 缺陷小鼠中天然存在的 Th1 细胞的发育并未受到损害。此外，Th1 细胞通常是由 Tyk2 缺陷的初始 CD4 T 细胞通过淋巴细胞减少诱导的增殖产生的。然而，所有这些 Th1 亚群，包括传统 Ag 诱导的 Th1 细胞，都以 Tyk2 依赖性方式响应 IL-12 产生 IFN-γ。重要的是，任何 Th1 亚群的这种 Tyk2 依赖性旁观者 IFN-γ 产生都能提供针对单核细胞增生利斯特氏菌感染的早期保护。因此，Tyk2 介导的 IL-12 信号传导对于不同 Th1 细胞亚群的发育有不同的需求，但同样会诱导其旁观者 IFN-g 的产生，从而有助于宿主对细胞内细菌感染的先天防御。
IL-12, which is produced in response to intracellular bacteria, such as Listeria monocytogenes, promotes the development of pathogen-specific Th1 cells that play an important role in host defense. However, it has also been known that CD44(high) memory-phenotype CD4 T cells with Th1 functions naturally occur in naive mice, and that lymphopenia-induced proliferation of naive CD4 T cells generates memory-phenotype CD4 T cells with Th1 functions, although their differentiation mechanism and contribution to host defense are unclear. In this study, we analyzed the development and the functions of the different subsets of Th1 cells by using mice lacking tyrosine kinase 2 (Tyk2), a member of the Janus kinase family critically involved in IL-12 signaling. In contrast with the case of conventional Ag-specific Th1 cells, the development of naturally occurring Th1 cells was not impaired in Tyk2-deficient mice. In addition, Th1 cells were normally generated from Tyk2-deficient naive CD4 T cells via lymphopenia-induced proliferation. Nevertheless, all these Th1 subsets, including conventional Ag-induced Th1 cells, produced IFN-gamma in response to IL-12 in a Tyk2-dependent manner. Importantly, such Tyk2-dependent bystander IFN-gamma production of any Th1 subsets conferred early protection against L. monocytogenes infection. Thus, Tyk2-mediated IL-12 signaling is differentially required for the development of different Th1 cell subsets but similarly induces their bystander IFN-g production, which contributes to innate host defense against infection with intracellular bacteria.