Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.
Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.
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DOI：
10.1371/journal.ppat.1002984
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Chen ZW
中科院分区：
文献类型：
--
作者：
Qiu Y;Chen J;Liao H;Zhang Y;Wang H;Li S;Luo Y;Fang D;Li G;Zhou B;Shen L;Chen CY;Huang D;Cai J;Cao K;Jiang L;Zeng G;Chen ZW
在结核分枝杆菌（Mtb）感染过程中，由T细胞免疫球蛋白和含粘蛋白结构域的分子3（Tim-3）调节的T细胞免疫应答仍然知之甚少。在这里，我们发现活动性TB患者表现出Tim-3表达的CD 4+和CD 8 + T细胞的数量增加，其优先显示极化效应记忆表型。与效应表型一致，Tim-3+ CD 4+和Tim-3+ CD 8 + T细胞亚群显示出比Tim-3−对应物更大的产生Th 1/Th 22细胞因子和CTL效应分子的效应功能，并且Tim-3表达T细胞更明显地限制了巨噬细胞中的细胞内Mtb复制。表达Tim-3的T细胞的效应子功能增加与细胞活化信号传导一致，因为Tim-3+ CD 4+和Tim-3+ CD 8 + T细胞亚群表达比Tim-3对照高得多的磷酸化信号传导分子p38、stat 3、stat 5和Erk 1/2水平。机制实验表明，Tim-3的siRNA沉默或可溶性Tim-3处理干扰膜Tim-3-配体相互作用减少了Tim-3表达T细胞的IFN-γ和TNF-α的从头产生。此外，通过抗体交联膜Tim-3刺激Tim-3信号传导途径增强了CD 4+和CD 8 + T细胞产生IFN-γ的效应子功能，表明Tim-3信号传导有助于驱动活动性TB患者中更强的效应子功能。因此，这项研究揭示了Tim-3调节T细胞免疫反应的一种以前未知的机制，这些发现可能对结核病的潜在免疫干预具有意义。结核病（TB）是由结核分枝杆菌（Mtb）感染引起的传染病，仍然是世界范围内发病率和死亡率的主要原因。虽然需要产生Th 1或细胞毒性细胞因子的CD 4+和CD 8 + T细胞效应子功能来建立抗分枝杆菌免疫，但CD 4+和CD 8 + T细胞的抗分枝杆菌效应子功能不足或未能建立抗分枝杆菌效应子功能可能导致针对TB的免疫受损。因此，阐明结核分枝杆菌特异性CD 4+和CD 8 + T细胞在结核分枝杆菌感染免疫应答中的功能特征和调控途径是重要的。据推测，T细胞免疫球蛋白和含粘蛋白结构域的分子3（Tim-3）可能代表T细胞耗竭标志物，并且Tim-3在T细胞上的表达可能与细胞因子分泌的进行性丧失有关。因此，T细胞上的Tim-3表达可能与T细胞功能障碍和疾病致病事件相关。然而，在人类结核病中由Tim-3调节的T细胞免疫应答仍然知之甚少。在这里，我们发现，在活动性人类TB疾病中Tim-3表达的上调允许CD 4+和CD 8 + T细胞安装更强，但不受损的抗分枝杆菌效应子功能。因此，这项研究揭示了Tim-3调节T细胞免疫应答的一种以前未知的机制，对结核病的诊断和治疗具有重要意义。
T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-3− counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-γ and TNF-α by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-γ production by CD4+ and CD8+ T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a leading cause of morbidity and mortality worldwide. While CD4+ and CD8+ T-cell effector functions producing Th1 or cytotoxic cytokines are required to mount anti-mycobacterial immunity, insufficiency or failure to mount anti-mycobacterial effector functions by CD4+ and CD8+ T cells may lead to impaired immunity against TB. Therefore, it is important to elucidate functional characteristics and regulatory pathways for Mtb-specific CD4+ and CD8+ T cells during immune responses to Mtb infection. It was postulated that T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) might represent a T-cell exhaustion marker, and expression of Tim-3 on T cells may be linked to progressive loss of secretion of cytokines. Thus, Tim-3 expression on T cells might correlate with T-cell dysfunction and disease pathogenic events. However, T-cell immune responses modulated by Tim-3 in human TB disease remain poorly understood. Here, we found that up-regulation of Tim-3 expression in active human TB disease allows CD4+ and CD8+ T cells to mount stronger, but not impaired, anti-mycobacterium effector functions. This study therefore uncovers a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and has an important implication for TB diagnostics and therapy.
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