Baumann Claudia, Bonilla Weldy V, Fröhlich Anja, Helmstetter Caroline, Peine Michael, Hegazy Ahmed N, Pinschewer Daniel D, Löhning Max
Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Rheumatism Research Center Berlin, 10117 Berlin, Germany;
Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland; and.
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4056-61. doi: 10.1073/pnas.1418549112. Epub 2015 Mar 17.
During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4(+) T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4(+) T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.
在感染过程中，损伤相关分子模式（即所谓的“警报素”）的释放协调免疫反应。警报素白细胞介素-33（IL-33）在多种病理过程中发挥作用。释放后，IL-33通过其受体ST2发出信号，据报道ST2仅在Th2和调节性亚群的CD4(+) T细胞上表达。在此我们表明，在淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染期间，体外和体内分化时Th1效应细胞也表达ST2。与Th2细胞上组成性表达的ST2不同，Th1细胞上ST2的表达是短暂的，且标记的是高度活化的效应细胞。病毒特异性Th1细胞上ST2的表达依赖于Th1相关转录因子T-bet和STAT4。在混合骨髓嵌合小鼠和过继性细胞转移实验中，ST2缺陷均导致LCMV特异性Th1效应反应的T细胞内在损伤。ST2缺陷的病毒特异性CD4(+) T细胞显示出增殖受损、Th1效应分化受损以及抗病毒细胞因子产生受损。因此，这些细胞几乎不介导病毒诱导的免疫病理。所以，IL-33作为关键的直接辅助因子驱动抗病毒Th1效应细胞活化，这对疫苗接种策略和免疫治疗方法具有重要意义。
