The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse.
The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse.
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DOI：
10.1126/scisignal.aba0717
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发表时间：
2021-06-15
影响因子：
7.3
通讯作者：
Kane, Lawrence P.
中科院分区：
文献类型：
--
作者：
Kataoka, Shunsuke;Manandhar, Priyanka;Lee, Judong;Workman, Creg J.;Banerjee, Hridesh;Szymczak-Workman, Andrea L.;Kvorjak, Michael;Lohmueller, Jason;Kane, Lawrence P.
跨膜蛋白Tim-3的表达在经历慢性活化的失调T细胞上增加，包括在慢性感染期间和实体瘤中。因此，Tim-3通常被认为是一种抑制性蛋白。我们和其他人先前报道，在某些情况下，Tim-3在T细胞（和其他细胞）中发挥矛盾的共刺激活性，包括增强核糖体S6蛋白的磷酸化。在这里，我们研究了上游信号通路，控制Tim-3介导的增加磷酸化的S6在T细胞。我们还确定了Tim-3相对于T细胞免疫突触的定位及其对下游信号传导的影响。Tim-3向免疫突触的募集完全由跨膜结构域介导，其替换损害Tim-3共刺激T细胞受体（TCR）依赖性S6磷酸化的能力。此外，Tim-3胞质结构域在嵌合抗原受体中的免疫突触的强制定位仍然能够激活T细胞。总之，我们的发现与Tim-3在急性条件下增强TCR近端信号传导的模型一致。
Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
30.5
作者：
Chiba, Shigeki;Baghdadi, Muhammad;Akiba, Hisaya;Yoshiyama, Hironori;Kinoshita, Ichiro;Dosaka-Akita, Hirotoshi;Fujioka, Yoichiro;Ohba, Yusuke;Gorman, Jacob V.;Colgan, John D.;Hirashima, Mitsuomi;Uede, Toshimitsu;Takaoka, Akinori;Yagita, Hideo;Jinushi, Masahisa
通讯作者：
Jinushi, Masahisa
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.4
作者：
Gorman, Jacob V.;Colgan, John D.
通讯作者：
Colgan, John D.