IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection

Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.调节性T（Regulatory T, Treg）细胞可抑制针对病毒感染的过度免疫应答，从而避免免疫病理损伤。巨细胞病毒（Cytomegaloviruses, CMVs）属于疱疹病毒，通常在免疫功能健全的宿主中引发无症状感染，并诱导可抵御CMV相关疾病的强效细胞免疫应答。目前尚不明确，这类持续性病毒如何既能在急性感染阶段，又能在终身持续感染及病毒再激活过程中，避免诱发免疫病理损伤。这一现象的成因，可能既包括病毒通过多种免疫逃逸策略特异性调控免疫应答，也可能与CMV感染诱导Treg细胞生成有关。本研究证实，在感染鼠巨细胞病毒（murine CMV, MCMV）的小鼠体内，肝脏Treg细胞会被显著诱导扩增。耗竭Treg细胞会导致小鼠出现严重肝炎及肝损伤，但病毒载量未发生明显变化。此外，肝脏Treg细胞高表达ST2——这是组织警报素IL-33的细胞受体，而感染小鼠的肝脏中IL-33的表达会显著上调。本研究证实，IL-33信号通路对于MCMV感染后Treg细胞的聚集增殖至关重要；与感染对照组小鼠相比，ST2缺陷型小鼠会表现出更严重的肝脏病理损伤及更高的死亡率。上述结果表明，在CMV感染过程中，IL-33对于肝脏Treg细胞的免疫抑制功能具有关键作用。