Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
Immunol Cell Biol. 2011 Oct;89(7):786-91. doi: 10.1038/icb.2011.1. Epub 2011 May 3.
Protective immune responses during Mycobacterium tuberculosis (M. tuberculosis) infection are regulated at multiple levels and critically dependent on the balance in the secretion of pro-inflammatory and regulatory cytokines. A key factor that governs this balance at the cellular level is suppressors of cytokine signaling (SOCS). We recently demonstrated that toll-like receptor 2 and dendritic cell (DC)-SIGNR1 differentially regulate SOCS1 expression in DCs during M. tuberculosis infection. This consecutively regulated IL-12 production and determined M. tuberculosis survival. In this study, we characterized the role of SOCS1 in regulating effector responses from CD4(+) and CD8(+) T cells during M. tuberculosis infection. Our data indicate that T cells from M. tuberculosis-infected mice show increased and differential association of SOCS1 with CD3 and CD28, when compared with uninfected mice. While SOCS1 displays increased association with CD3 than CD28 in CD4(+) T cells; SOCS1 is associated more with CD28 than CD3 in CD8(+) T cells. Further, SOCS1 shows increased association with IL-12 and IL-2 receptors in both CD4(+) and CD8(+) T cells from infected mice when compared with naive mice. Silencing SOCS1 in T cells increased signal transduction from T cell receptor (TCR) and CD28 with enhanced activation of key signaling molecules and proliferation. Significantly, SOCS1-silenced T cells mediated enhanced clearance of M. tuberculosis inside macrophages. Finally, adoptive transfer of SOCS1-silenced T cells in M. tuberculosis-infected mice mediated significant reduction in M. tuberculosis loads in spleen. These results exemplify the negative role played by SOCS1 during T cell priming and effector functions during M. tuberculosis infection.
结核分枝杆菌（M. tuberculosis）感染期间的保护性免疫反应在多个水平上受到调节，并且严重依赖于促炎细胞因子和调节性细胞因子分泌的平衡。在细胞水平上控制这种平衡的一个关键因素是细胞因子信号转导抑制因子（SOCS）。我们最近证明，Toll 样受体 2 和树突状细胞（DC）-SIGNR1 在分枝杆菌感染期间在 DC 中差异调节 SOCS1 的表达。这连续调节了 IL-12 的产生并决定了分枝杆菌的存活。在这项研究中，我们表征了 SOCS1 在调节分枝杆菌感染期间 CD4(+)和 CD8(+)T 细胞效应反应中的作用。我们的数据表明，与未感染的小鼠相比，分枝杆菌感染的小鼠的 T 细胞显示 SOCS1 与 CD3 和 CD28 的增加和差异关联。虽然 SOCS1 在 CD4(+)T 细胞中与 CD3 的关联比 CD28 多；SOCS1 在 CD8(+)T 细胞中与 CD28 的关联比 CD3 多。此外，与未感染的小鼠相比，感染小鼠的 CD4(+)和 CD8(+)T 细胞中 SOCS1 与 IL-12 和 IL-2 受体的关联增加。在 T 细胞中沉默 SOCS1 可增加 T 细胞受体（TCR）和 CD28 的信号转导，从而增强关键信号分子的激活和增殖。重要的是，沉默 SOCS1 的 T 细胞介导了巨噬细胞内分枝杆菌的清除增强。最后，在分枝杆菌感染的小鼠中过继转移沉默 SOCS1 的 T 细胞可显著降低脾脏中的分枝杆菌负荷。这些结果例证了 SOCS1 在分枝杆菌感染期间 T 细胞启动和效应功能中发挥的负作用。
