NFAT1 and NFAT2 differentially regulate CTL differentiation upon acute viral infection

Abstract

CD8+ T cell differentiation orchestrated by transcription regulators is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs respectively. The transcription factor Nuclear Factor of Activated T cells (NFAT) family members are known for their roles in T cell development and activation but still largely undetermined in CD8+ T cell differentiation in vivo. Here, we interrogated the role of two NFAT family members, NFAT1 and NFAT2, in the effector and memory phase of CD8+ T cell differentiation using LCMVArm acute infection model. We found that NFAT1 is critical for effector population generation whereas NFAT2 is required for promoting memory CTLs in a cell-intrinsic manner. Moreover, we found that mice lacking both NFAT1 and NFAT2 in T cells display a significant increase in KLRG1hi and CD127hi population and are unable to clear an acute viral infection. NFAT-deficient CTLs showed different degrees of impaired IFN-g and TNF-a expression with NFAT1 being mainly responsible for IFN-g production as well as for antigen-specific cytotoxicity. To further comprehend the molecular mechanisms behind this differential CTL commitment upon deficiency of NFAT members, we performed RNA-seq analysis. Our results have identified genes uniquely regulated by NFAT1 or NFAT2, and we are in the process of further understanding how this differential transcriptome translates into the observed distinct CTL differentiation. Overall, our results suggest that NFAT1 and NFAT2 have distinct roles in mediating CD8+ T cell differentiation and function.