RyR2-mediated calcium signaling regulates T-cell activation and Th1 differentiation.

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.