Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Immunohorizons. 2020 Nov 10;4(11):701-712. doi: 10.4049/immunohorizons.2000059.
CD4 T cells play critical roles during chronic viral infections, but the factors that regulate these responses remain incompletely defined. During chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV13), the TNFR family member GITR plays a critical CD4 T cell-intrinsic role in allowing T cell accumulation and viral control. Previously, RNA sequencing of GITR and GITR T cells sorted from the spleen of mice at day 3 of LCMV13 infection identified the chemokine receptor CX3CR1 as increased by GITR signaling in CD4 T cells. In this study, we evaluated the role of CX3CR1 on CD4 T cells during LCMV13 infection. CX3CR1 expression is induced on Ag-specific CD4 T cells upon Ag stimulation, and GITR signaling further increases the level of CX3CR1 expression. CX3CR1 marks the most differentiated T-bet, Th1 effector population. Adoptively transferred CX3CR1 SMARTA cells had slightly reduced expression of T-bet and IFN-γ per cell compared with their CX3CR1 counterparts but showed no deficit in accumulation in the spleen, lung, or liver. In mixed-radiation chimeras reconstituted with CX3CR1 and CX3CR1 bone marrow, CX3CR1 CD4 T cells showed a marginal deficit in tissue-resident memory T cell numbers compared with the CX3CR1 T cells. CX3CR1 may limit acquisition of the tissue-resident memory T cell phenotype because of its effects on increasing T-bet expression, albeit these small effects are unlikely to be of major biological significance. Taken together, these studies show that CX3CR1 marks the most highly differentiated CD4 Th1 effector population but is largely dispensable for CD4 T cell responses during chronic viral infection.
CD4 T 细胞在慢性病毒感染中发挥着关键作用，但调节这些反应的因素仍不完全明确。在淋巴细胞性脉络丛脑膜炎病毒克隆 13（LCMV13）慢性感染的小鼠中，TNFR 家族成员 GITR 在允许 T 细胞积累和控制病毒方面发挥着关键的 CD4 T 细胞内在作用。先前，对 GITR 和 GITR 细胞从感染 LCMV13 第 3 天的小鼠脾脏中分选后的 RNA 测序，鉴定出趋化因子受体 CX3CR1 在 CD4 T 细胞中由 GITR 信号上调。在这项研究中，我们评估了 CX3CR1 在 LCMV13 感染期间对 CD4 T 细胞的作用。抗原刺激后，抗原特异性 CD4 T 细胞表达 CX3CR1，GITR 信号进一步增加 CX3CR1 的表达水平。CX3CR1 标记出最分化的 T-bet、Th1 效应细胞群体。与 CX3CR1 对照细胞相比，过继转移的 CX3CR1 SMARTA 细胞的 T-bet 和 IFN-γ 表达水平略低，但在脾脏、肺或肝脏中的积累没有缺陷。在用 CX3CR1 和 CX3CR1 骨髓重建的混合辐射嵌合体中，与 CX3CR1 T 细胞相比，CX3CR1 CD4 T 细胞的组织驻留记忆 T 细胞数量略有减少。由于其对增加 T-bet 表达的影响，CX3CR1 可能限制了组织驻留记忆 T 细胞表型的获得，尽管这些小影响不太可能具有主要的生物学意义。综上所述，这些研究表明，CX3CR1 标记出最高度分化的 CD4 Th1 效应细胞群体，但在慢性病毒感染期间，对 CD4 T 细胞反应的作用在很大程度上是可有可无的。
