Interleukin-2 drives distinct regulation and function of BATF3 and BATF during naive CD8 T cell priming 4734

Abstract Description CD8+ T cell activation triggers chromatin remodeling and transcription factor (TF) binding that drives differentiation into multiple effector (TEFF) and memory (TMEM) cell phenotypes. T cell receptor (TCR) stimulation induces chromatin accessibility of cis-regulatory regions encoding motifs recognized by TFs in the Basic Leucine Zipper (bZIP) family. However, it is unclear how these TFs drive transcription that promotes development of TEFF and TMEM cells. Here we demonstrate that primary TCR stimulation upregulated the closely related bZIP TFs BATF and BATF3, but that their regulation and function were distinct. The transcription of both genes was strongly induced during TCR stimulation, and Batf3 (not Batf) required both the TF RUNX3 and stimulation with IL-2. Retroviral expression of constitutively active Stat5a induced Batf3 when IL-2 stimulation was blocked. BATF3 was required in CD8+ T cells during primary TCR stimulation to promote chromatin accessibility of cis-regulatory regions that become accessible at early times after acute viral infection, many of which remain stably accessible in tissue-resident memory cells, but do not remain accessible in mature TEFF and TMEM cells in the spleen. Notably, these regions were largely distinct from those that required BATF. These results suggest that BATF3 is specifically controlled by IL-2 signaling and Stat5a during CD8+ T cell priming, and that BATF3 and BATF have distinct functions that induce TEFF and TMEM CD8+ T cell fates. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)