Distinct domains in the transcription factor Runx3 mediate differential antiviral CD8 T cell phenotypes

Abstract

Abstract Runx3 is one of three Runt-family transcription factors (TF) that control gene expression by modifying chromatin structure. Upon initial T cell receptor stimulation, Runx3 drives chromatin accessibility found in mature circulating and tissue-resident memory CD8 T cells. Runx3-deficient cells preferentially develop a KLRG1 hiCD127 loterminal effector (TE) phenotype, whereas Runx3 overexpression promotes formation of KLRG1 loCD127 hiclassical memory precursor (MP) cells and KLRG1 hiCD127 hidouble positive (DP) effector cells during the effector phase. Runt-family TFs harbor activation, inhibition, and VWRPY domains that interact with distinct chromatin modifying proteins, but their individual contributions to Runx3-driven phenotypes in effector CD8 T cells are unresolved. Here we examined Runx3-deficient CD8 T cells complemented with wildtype or Runx3-domain deleted mutants during viral infection. The activation and VWRPY domains were each required to repress the TE cell phenotype. However, the activation, but not VWRPY domain, was necessary to repress high T-bet expression. Moreover, the larger gene expression pattern resulting from complementation with the VWRPY mutant was generally similar to that of wildtype Runx3. In addition, we found that wildtype Runx3 repressed the TF Tox and upregulated PD-1 and Tim-3, which required its inhibition domain. Runx3 lacking its inhibition domain also generated more MP cells and more highly induced CD127 compared to wildtype Runx3. These results indicate that distinct domains in Runx3 mediate differential control of gene expression in effector CD8 T cells, and might suggest avenues for targeting Runx3 domains to elicit specific memory T cell phenotypes. Supported by grants from NIAID (R01 AI095634, P01 AI145815)