Memory regulatory T cells (mTregs) have been demonstrated to persist long-term in hosts after the resolution of primary influenza A virus (IAV) infection. However, whether such IAV infection-experienced (IAV-experienced) mTregs differentiate into a phenotypically and functionally distinct Treg subset and what function they play at the infection site remains poorly defined. In this study, we characterized the phenotype, examined the responsiveness and assessed the suppressive function of IAV-experienced memory Tregs (mTregs). In comparison with inexperienced naïve Tregs (nTregs), mTregs exhibited elevated expression of CD39, CD69, CD103, cytotoxic T lymphocyte-associated antigen-4, leukocyte function-associated antigen-1 and programmed cell death-1 and could be activated in an antigen-specific manner in vitro and in vivo. When mTregs and nTregs were adoptively cotransferred into recipient mice, mTregs had a competitive advantage in migrating to the IAV-infected lungs. mTregs were more capable of controlling in vitro proliferation of CD4+ and CD8+ T cells and suppressed CD40 and CD86 upregulation on bone marrow-derived dendritic cells. Adoptively transferred mTregs, but not adoptively transferred nTregs, significantly attenuated body weight loss, lung pathology and immune cell infiltration into the infected lungs after IAV infection. These results suggest that mTregs generated after IAV infection differentiate into a phenotypically distinct and functionally enhanced Treg subset that can be activated in an antigen-specific manner to exert immunosuppression. We propose vaccination to induce such mTregs as a potential novel strategy to protect against severe IAV infection.

中文翻译：

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记忆调节性T细胞位于肺部并控制A型流感病毒感染。

事实证明，在解决原发性甲型流感病毒（IAV）感染后，记忆调节性T细胞（mTreg）可以在宿主中长期存在。然而，这种经历IAV感染（IAV经历）的mTregs是否分化为表型和功能上不同的Treg亚型，以及它们在感染部位所起的作用仍不清楚。在这项研究中，我们表征了表型，检查了反应性并评估了IAV经历的记忆Tregs（mTregs）的抑制功能。与没有经验的幼稚Tregs（nTregs）相比，mTregs表现出CD39，CD69，CD103，细胞毒性T淋巴细胞相关抗原4，白细胞功能相关抗原1和程序性细胞死亡1表达升高，并且可以在抗原中被激活体内和体外的特异性方式。当将mTregs和nTregs过继共转移到受体小鼠中时，mTregs在迁移到感染IAV的肺部时具有竞争优势。mTregs更能控制CD4 +和CD8 + T细胞的体外增殖，并抑制骨髓来源的树突状细胞上CD40和CD86的上调。在IAV感染后，过继转移的mTregs而非过继转移的nTregs显着减轻了体重减轻，肺部病理和免疫细胞向感染肺的浸润。这些结果表明，IAV感染后产生的mTregs分化为表型不同且功能增强的Treg亚型，可通过抗原特异性方式激活以发挥免疫抑制作用。