Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection.
Tim-3 negatively regulates cytotoxicity in exhausted CD8+ T cells in HIV infection.
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DOI：
10.1371/journal.pone.0040146
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ostrowski MA
中科院分区：
文献类型：
--
作者：
Sakhdari A;Mujib S;Vali B;Yue FY;MacParland S;Clayton K;Jones RB;Liu J;Lee EY;Benko E;Kovacs C;Gommerman J;Kaul R;Ostrowski MA
细胞毒性CD8+ T细胞（ctl）通过释放含有穿孔素和颗粒酶的颗粒来抑制病毒感染。T细胞“衰竭”是包括HIV在内的慢性持续性病毒感染的标志。在慢性进行性感染中，抑制调节分子T细胞免疫球蛋白和粘蛋白结构域3 （Tim-3）被诱导于hiv特异性T细胞。这些表达Tim-3的T细胞在增殖或产生细胞因子的能力方面功能失调。在这项研究中，我们评估了Tim-3表达对HIV感染背景下CD8+ T细胞毒性能力的影响。我们通过检测Tim-3+ CD8+ T细胞制造穿孔素的能力和Tim-3+ CD8+ T细胞直接杀伤自身HIV感染的CD4+靶细胞的能力来研究表达Tim-3的T细胞的细胞毒能力。令人惊讶的是，Tim-3+ CD8+ T细胞维持较高水平的穿孔素，穿孔素主要以颗粒相关（储存）构象存在，并表达高水平的T-bet。然而，这些细胞在脱颗粒能力上也存在缺陷。阻断Tim-3信号通路可增强慢性进展者的HIV特异性CD8+ T细胞的细胞毒性能力；a)它们的脱颗粒能力，b)它们释放穿孔素的能力，c)它们将活化的颗粒酶b靶向表达CD4+ T细胞的HIV抗原的能力，d)它们抑制CD4+ T细胞感染HIV的能力。在后一种效应中，阻断Tim-3通路可将慢性进展者CD8+ T细胞的细胞毒性提高到非常接近病毒控制者T细胞的水平。因此，Tim-3受体除了作为细胞因子产生和ctl增殖功能的终结者外，还可以通过抑制脱粒、穿孔素和颗粒酶的分泌来下调CD8+ T细胞的细胞毒功能。
Cytotoxic CD8+ T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell ‘exhaustion’ is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8+ T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3+ CD8+ T cells to make perforin and 2) the direct ability of Tim-3+ CD8+ T cells to kill autologous HIV infected CD4+ target cells. Surprisingly, Tim-3+ CD8+ T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8+ T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4+ T cells and d) their ability to suppress HIV infection of CD4+ T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8+ T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8+ T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.
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影响因子：
5.4
作者：
Anderson, Ana C.;Lord, Graham M.;Dardalhon, Valerie;Lee, David H.;Sabatos-Peyton, Catherine A.;Glimcher, Laurie H.;Kuchroo, Vijay K.
通讯作者：
Kuchroo, Vijay K.
影响因子：
168.9
作者：
Hess, C;Altfeld, M;Luster, AD
通讯作者：
Luster, AD
影响因子：
5.4
作者：
KAGI, D;LEDERMANN, B;ZINKERNAGEL, RM
通讯作者：
ZINKERNAGEL, RM
影响因子：
20.3
作者：
Deeks, SG;Kitchen, CMR;Hecht, FM
通讯作者：
Hecht, FM
影响因子：
3.8
作者：
Andersson, J;Behbahani, H;Fehniger, TE
通讯作者：
Fehniger, TE