Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany.
Front Immunol. 2019 Aug 7;10:1833. doi: 10.3389/fimmu.2019.01833. eCollection 2019.
Memory CD8 cytotoxic T lymphocytes (CTLs) can protect against viral reinfection. However, the signals driving rapid memory CTL reactivation have remained ill-defined. Viral infections can trigger the release of the alarmin interleukin-33 (IL-33) from non-hematopoietic cells. IL-33 signals through its unique receptor ST2 to promote primary effector expansion and activation of CTLs. Here, we show that the transcription factor STAT4 regulated the expression of ST2 on CTLs and in primary infections with lymphocytic choriomeningitis virus (LCMV). In the primary antiviral response, IL-33 enhanced effector differentiation and antiviral cytokine production in a CTL-intrinsic manner. Further, using sequential adoptive transfers of LCMV-specific CD8 T cells, we deciphered the IL-33 dependence of circulating memory CTLs at various stages of their development. IL-33 was found dispensable for the formation and maintenance of memory CTLs, and its absence during priming did not affect their recall response. However, in line with the CTL-boosting role of IL-33 in primary LCMV infections, circulating memory CTLs required IL-33 for efficient secondary expansion, enhanced effector functions, and virus control upon challenge infection. Thus, beyond their effector-promoting activity in primary immune reactions, innate alarmin signals also drive memory T cell recall responses, which has implications for immunity to recurrent diseases.
记忆性 CD8 细胞毒性 T 淋巴细胞 (CTL) 可预防病毒再感染。然而，驱动记忆性 CTL 快速激活的信号仍未明确。病毒感染可触发非造血细胞中警报素白细胞介素-33 (IL-33) 的释放。IL-33 通过其独特的受体 ST2 信号转导，促进初始效应细胞的扩增和 CTL 的激活。在这里，我们发现转录因子 STAT4 调节 CTL 上 ST2 的表达，并在淋巴细胞性脉络丛脑膜炎病毒 (LCMV) 的原发性感染中调节其表达。在抗病毒的初始反应中，IL-33 以 CTL 内在的方式增强效应细胞分化和抗病毒细胞因子的产生。此外，我们通过 LCMV 特异性 CD8 T 细胞的连续过继转移，解析了 IL-33 在循环记忆 CTL 发育的各个阶段的依赖性。发现 IL-33 对于记忆 CTL 的形成和维持并不必需，其在初始阶段的缺失也不影响它们的记忆反应。然而，与 IL-33 在原发性 LCMV 感染中增强 CTL 的作用一致，循环记忆 CTL 需要 IL-33 来进行有效的二次扩增、增强效应功能，并在再次感染时控制病毒。因此，警报素信号除了在原发性免疫反应中具有促进效应细胞的作用外，还驱动记忆性 T 细胞的记忆反应，这对复发性疾病的免疫具有重要意义。
