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 CD127hi population and are unable to clear an acute viral infection. NFAT-deficient CTLs showed different degrees of impaired IFN-γ and TNF-α expression with NFAT1 being mainly responsible for IFN-γ production upon ex-vivo stimulation as well as for antigen-specific cytotoxicity. Our results suggest that NFAT1 and NFAT2 have distinct roles in mediating CD8+ T cell differentiation and function.
Highlights
CD8+ T cells are pivotal in combating intracellular pathogens and for tumor immune surveillance [1, 2]
We examined the role of NFAT1 and NFAT2 in CTL differentiation and function using an acute lymphocytic choriomeningitis virus Armstrong strain (LCMVArm ) infection model [28, 29]
We found that NFAT1 KO mice have increased spleen cellularity, whereas NFAT2 TKO and NFAT1/2 DKO mice have significant fewer splenocytes compared to WT controls (Figure S1B)
Summary
CD8+ T cells are pivotal in combating intracellular pathogens and for tumor immune surveillance [1, 2]. A transcription factor responsible for mediating CD8+ T cell commitment in the thymus by antagonizing ThPok, which drives CD4+ Th cell fate [17], has been recently implicated in the early TCR signaling events during priming to promote the accessibility of chromatin containing IRF, bZIP, and PRDM1 binding motifs resulting in the strengthening of memory population differentiation [18]. Despite the knowledge on how these transcription factors regulate CTL differentiation in vivo, the exact mechanisms that set off the effector and memory CD8+ T cells development are still unclear, especially those transcription factors downstream of early TCR signaling events. The defect in CTL differentiation was cellintrinsic, as evidenced by both mixed bone marrow chimera experiments and adoptive transfer of NFAT-deficient antigenspecific P14 TCR transgenic cells
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