Interferon gamma-induction of TH1-like regulatory T cells controls anti-viral responses

Abstract: Regulatory T cells (Tregs) are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage during immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. We report that Tregs acquire an effector-like state, yet remain stable and functional, when exposed to IFNγ during chronic infection with lymphocytic choriomeningitis (LCMV) and Influenza A virus (IAV). Mechanistically, Treg-restricted-deletion of the IFNγ receptor 1 (IFNGR1), but not the IL12 receptor, prevented TH1-like polarization (decreased expression of T-bet, CXCR3 and IFNγ) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Tregs limited CD8+ T cell effector function, proliferation and memory formation during chronic and acute infection. These findings provide fundamental insights into how Tregs sense inflammatory cues from the environment (IFNγ) during viral infection to provide immune guidance to the effector T cell response, to prevent prolonged immunoinflammatory responses and shape the quality of the memory response. Splenic Tregs and Tetramer+ CD8+ T cells were harvested from Foxp3Cre-YFP or Ifngr1L/LFoxp3Cre-YFP mice that remained naïve or were infected with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl 13) for 16d

摘要：调节性T细胞（Regulatory T cells, Tregs）是一类具有免疫抑制功能的细胞群，通过分泌抗炎细胞因子、表达抑制性受体以及代谢扰动等方式，维持外周免疫耐受并在免疫病理过程中防止组织损伤。本研究发现，在慢性淋巴细胞性脉络丛脑膜炎病毒（Lymphocytic choriomeningitis virus, LCMV）与甲型流感病毒（Influenza A virus, IAV）感染过程中，Tregs暴露于干扰素γ（IFNγ）时会获得效应样状态，但仍保持稳定且具备正常功能。从机制上来说，特异性敲除Tregs中的干扰素γ受体1（IFNγ receptor 1, IFNGR1）而非白细胞介素12受体（IL12 receptor），可阻止Tregs向T辅助细胞1样（TH1-like）极化——表现为T-bet、CXCR3与IFNγ的表达下调，并促进其向T辅助细胞2样（TH2-like）极化——表现为GATA-3、CCR4与IL4的表达上调。TH1样Tregs在慢性与急性感染过程中，可抑制CD8+ T细胞的效应功能、增殖与记忆细胞形成。本研究结果为病毒感染过程中Tregs如何感知环境中的炎症信号（IFNγ）、从而对效应T细胞应答提供免疫调控指导，以防止过度免疫炎症反应并塑造记忆应答的质量，提供了基础性的认知。本研究从未致敏（naïve）或经淋巴细胞性脉络丛脑膜炎病毒克隆13型（LCMV Clone 13, Cl 13）感染16天的Foxp3Cre-YFP或Ifngr1L/LFoxp3Cre-YFP小鼠中，采集了脾脏Tregs与四聚体阳性（Tetramer+）CD8+ T细胞。