Acute stimulation generates Tim-3-expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function
Acute stimulation generates Tim-3-expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function
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DOI：
10.1111/imm.12890
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发表时间：
2018-07-01
期刊：
影响因子：
6.4
通讯作者：
Colgan, John D.
中科院分区：
文献类型：
--
作者：
Gorman, Jacob V.;Colgan, John D.
T细胞免疫球蛋白和粘蛋白结构域3（Tim-3）是由辅助性T细胞1型（Th 1）效应CD 4 T细胞表达的表面受体，其对于防御细胞内病原体至关重要，并且已经涉及自身免疫性疾病。以前的研究表明，Tim-3表达使Th 1细胞更容易凋亡，也标志着由于慢性刺激而出现的功能受损的T细胞。然而，其他研究表明，表达Tim-3的Th 1细胞并不总是具有这些特性。为了进一步确定Tim-3和Th 1细胞功能之间的关系，我们分析了Th 1细胞表达Tim-3在体外短暂刺激或体内急性病毒感染反应的特征。正如预期的那样，培养的CD 4 T细胞在Th 1分化过程中开始表达Tim-3，二次刺激产生Tim-3（-）和Tim-3（+）部分，将其分离并进一步分析。当注射到幼稚小鼠中时，Tim-3（+）细胞下调Tim-3，并且与Tim-3（-）细胞相比同样存活良好。此外，Tim-3（-）和Tim-3（+）Th 1细胞在转移到随后感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）的未处理小鼠体内时具有相似的功能反应。在T细胞受体刺激后表达Tim-3的培养的Th 1细胞比Tim-3（-）对应物具有更大的表达特征性Th 1细胞因子的能力，并且显示出调节CD 4 T细胞功能的基因的差异表达。与这些发现一致，LCMV感染后产生的Tim-3（+）Th 1细胞相对于Tim-3（-）细胞显示出增强的效应子功能。这些结果表明，Tim-3表达的Th 1细胞响应于急性刺激可以标记细胞的功能，并具有增强的能力，产生细胞因子。
T-cell immunoglobulin and mucin domain 3 (Tim-3) is a surface receptor expressed by T helper type 1 (Th1) effector CD4 T cells, which are critical for defence against intracellular pathogens and have been implicated in autoimmune disease. Previous studies showed that Tim-3 expression makes Th1 cells more susceptible to apoptosis and also marks functionally impaired T cells that arise due to chronic stimulation. However, other studies suggested that Tim-3-expressing Th1 cells do not always have these properties. To further define the relationship between Tim-3 and Th1 cell function, we analysed the characteristics of Th1 cells that expressed Tim-3 in response to brief stimulation in vitro or an acute viral infection in vivo. As expected, cultured CD4 T cells began expressing Tim-3 during Th1 differentiation and secondary stimulation generated Tim-3(-) and Tim-3(+) fractions that were separated and further analysed. When injected into naive mice, Tim-3(+) cells down-regulated Tim-3 and survived equally well compared with Tim-3(-) cells. Further, Tim-3(-) and Tim-3(+) Th1 cells had similar functional responses when transferred into naive mice that were subsequently infected with lymphocytic choriomeningitis virus (LCMV). Cultured Th1 cells that expressed Tim-3 following T-cell receptor stimulation had a greater capacity to express signature Th1 cytokines than their Tim-3(-) counterparts and showed differential expression of genes that regulate CD4 T-cell function. Consistent with these findings, Tim-3(+) Th1 cells generated in response to LCMV infection displayed augmented effector function relative to Tim-3(-) cells. These results suggest that Tim-3 expression by Th1 cells responding to acute stimulation can mark cells that are functionally competent and have an augmented ability to produce cytokines.