Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.
Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.
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DOI：
10.1371/journal.ppat.1003442
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Rottenberg ME
中科院分区：
文献类型：
--
作者：
Carow B;Reuschl AK;Gavier-Widén D;Jenkins BJ;Ernst M;Yoshimura A;Chambers BJ;Rottenberg ME
细胞因子信号传导3抑制因子（SOCS3）负调控STAT3的激活，以响应几种细胞因子，如gp130- IL-6受体家族中的细胞因子。因此，SOCS3可能在对病原体的免疫反应中发挥重要作用。本研究探讨了SOCS3在结核分枝杆菌感染中的作用。所有的Socs3fl/fl LysM cre、Socs3fl/fl lck cre（分别具有SOCS3缺陷的髓细胞和淋巴细胞）和gp130F/F小鼠，gp130突变阻碍与SOCS3结合，均表现出对结核分枝杆菌感染的易感性增加。骨髓细胞中与gp130结合的SOCS3通过调节IL-6/STAT3信号传递对结核分枝杆菌感染的抗性。SOCS3对于巨噬细胞体外控制分枝杆菌是冗余的。相反，SOCS3在感染的巨噬细胞和dc中的表达阻止了il -6介导的TNF和IL-12分泌的抑制，并促进了体内CD4+细胞依赖性IFN-γ的及时表达。在T细胞中，SOCS3的表达对于不依赖gp130的结核分枝杆菌感染的控制是必需的，但对于减毒牛分枝杆菌BCG感染的控制和接种BCG的小鼠的结核分枝杆菌感染的控制都不需要。感染后，Socs3fl/ flck小鼠不同器官中γδ+ T细胞出现频率增加，γδ+ T细胞分泌IL-17增加。Socs3fl/ flck cre γδ+ T细胞破坏结核分枝杆菌感染的控制。因此，SOCS3在淋巴细胞或髓细胞中的表达对于通过离散机制抵抗结核分枝杆菌至关重要。结核病是一种由细胞内结核分枝杆菌感染引起的严重疾病。蛋白“细胞因子信号传导3抑制因子”（SOCS3）抑制细胞对几种细胞因子和生长因子的反应，这些细胞因子和生长因子通过STAT3转录因子发出信号。由于STAT3是免疫和炎症反应的主要控制者，我们研究了SOCS3在结核分枝杆菌感染控制中的作用。骨髓细胞或淋巴细胞中缺乏SOCS3表达的小鼠极易感染结核分枝杆菌，结果显示细菌水平升高、病理恶化和生存率降低。在髓细胞中，SOCS3阻碍了IL-6的有害作用。在缺乏SOCS3的情况下，IL-6阻碍抗原呈递细胞释放IL-12。在T细胞中，socs3介导的保护不依赖于IL-6信号，也不依赖抗原特异性T细胞分泌足够的IFN-γ。相反，SOCS3抑制了γδ+ T细胞的体内积累和IL-17的分泌。γδ+ T细胞部分解释了socs3缺陷T细胞小鼠对结核分枝杆菌感染的易感性。因此，SOCS3控制髓细胞和淋巴细胞的多种免疫机制，这是遏制结核分枝杆菌所必需的。
Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in M. tuberculosis infection was examined. All Socs3fl/fl LysM cre, Socs3fl/fl lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130F/F mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3fl/fl lck cre mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. Socs3fl/fl lck cre γδ+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms. Tuberculosis is a severe disease caused by infection with the intracellular bacteria Mycobacterium tuberculosis. The protein “suppressor of cytokine signalling 3” (SOCS3) inhibits the responses of cells to several cytokines and growth factors that signal via the STAT3 transcription factor. Since STAT3 is a major controller of immune and inflammatory responses, we studied the role of SOCS3 in the control of infection with M. tuberculosis. Mice deficient in the expression of SOCS3 either in myeloid or lymphoid cells were extremely susceptible to infection with M. tuberculosis as measured by elevated bacterial levels, worsened pathology and reduced survival. In myeloid cells, SOCS3 hindered a detrimental role of IL-6. In absence of SOCS3, IL-6 hampered the release of IL-12 by antigen-presenting cells. In T cells, SOCS3-mediated protection was independent of IL-6 signals, and of adequate IFN-γ secretion by antigen-specific T cells. Instead, SOCS3 inhibited the in vivo accumulation of, and the IL-17 secretion by γδ+ T cells. γδ+ T cells accounted in part for the susceptibility to M. tuberculosis infection of mice with SOCS3-deficient T cells. Thus, SOCS3 controls diverse immune mechanisms of myeloid and lymphoid cells that are required for containment of M. tuberculosis.
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