Orgun Nural N, Mathis Meredith A, Wilson Christopher B, Way Sing Sing
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
J Immunol. 2008 Mar 15;180(6):4109-15. doi: 10.4049/jimmunol.180.6.4109.
The differentiation of naive CD4 T cells into specific effector subsets is controlled in large part by the milieu of cytokines present during their initial encounter with Ag. Cytokines that drive differentiation of the newly described Th17 lineage have been characterized in vitro, but the cytokines that prime commitment to this lineage in response to infection in vivo are less clear. Listeria monocytogenes (Lm) induces a strong Th1 response in wild-type mice. By contrast, we demonstrate that in the absence of IL-12p40 (or IFN-gamma) and type I IFN receptor signaling, the Th1 Ag-specific CD4 T cell response is virtually abolished and replaced by a relatively low magnitude Th17-dominated response. This Th17 response was dependent on TGF-beta and IL-6. Despite this change in CD4 T cell response, neither the kinetics of the CD4 and CD8 T cell responses, the quality of the CD8 T cell response, nor the ability of CD8 T cells to mediate protection were affected. Thus, generation of protective CD8 T cell immunity was resilient to perturbations that replace a strong Th1-dominated to a reduced magnitude Th17-dominated Ag-specific CD4 T cell response.
初始CD4 T细胞向特定效应子亚群的分化在很大程度上受其初次接触抗原时存在的细胞因子环境控制。驱动新描述的Th17谱系分化的细胞因子已在体外得到表征，但在体内感染时引发对该谱系定向分化的细胞因子尚不清楚。单核细胞增生李斯特菌（Lm）在野生型小鼠中诱导强烈的Th1反应。相比之下，我们证明，在缺乏IL-12p40（或IFN-γ）和I型干扰素受体信号的情况下，Th1抗原特异性CD4 T细胞反应几乎被消除，并被相对较弱的以Th17为主导的反应所取代。这种Th17反应依赖于TGF-β和IL-6。尽管CD4 T细胞反应发生了这种变化，但CD4和CD8 T细胞反应的动力学、CD8 T细胞反应的质量以及CD8 T细胞介导保护的能力均未受到影响。因此，保护性CD8 T细胞免疫的产生对将以Th1为主导的强烈反应替换为以Th17为主导的较弱抗原特异性CD4 T细胞反应的扰动具有弹性。
