Zhai Di, Zheng Mingke, Huang Cheng, Wang Xiaobo, Shi Yan
Institute for Immunology, and School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
J Immunol. 2025 Jun 1;214(6):1247-1260. doi: 10.1093/jimmun/vkaf046.
T helper cell differentiation is one of the key developmental events in the peripheral immune regulations, resulting in better adaptation to the nature of infection and inflammation. While it is known that several factors are involved in this differentiation, including subsets of antigen-presenting cells, cytokine environment, and metabolic activation, how calcium signaling plays a role in this event has remained elusive and sometimes controversial. In this report, we show that ER membrane Ca2+ ion channel ryanodine receptor 2 (RyR2) may be an important regulator in this event. RyR2-deficient T cells show greater retention of Ca2+ in the ER and have reduced SOCE activation, leading a delayed entry of NFAT2 into the nuclei. This delay causes a significant bias toward Th1 both in cytokine profiles and in T-bet expression, likely as a result of increased Il12rb2 and Stat4 expression. Interestingly, such a bias permits better host protection against intracellular Listeria Monocytogenes infection. Our work suggests the possibility that RyR2 may be regulated in T-cell activation for biased Th polarization, which may provide a target for fine-tuning T-cell differentiation in future clinical settings.
辅助性T细胞分化是外周免疫调节中的关键发育事件之一，可更好地适应感染和炎症的性质。虽然已知多种因素参与这种分化，包括抗原呈递细胞亚群、细胞因子环境和代谢激活，但钙信号在这一过程中如何发挥作用仍不清楚，有时还存在争议。在本报告中，我们表明内质网（ER）膜Ca2+离子通道兰尼碱受体2（RyR2）可能是这一过程中的重要调节因子。RyR2缺陷型T细胞在内质网中对Ca2+的保留能力更强，且储存式钙内流（SOCE）激活减少，导致NFAT2进入细胞核的时间延迟。这种延迟在细胞因子谱和T-bet表达方面均导致向Th1的显著偏向，这可能是由于Il12rb2和Stat4表达增加所致。有趣的是，这种偏向使宿主对细胞内单核细胞增生李斯特菌感染具有更好的保护作用。我们的研究表明，RyR2可能在T细胞激活过程中受到调节，以实现偏向性的Th极化，这可能为未来临床环境中微调T细胞分化提供一个靶点。
