Distinct domains in RUNX3 dictate Tcf7 reactivation and Tox repression to generate protective memory CD8 T cells 4333

Abstract Description Memory CD8 T cells develop from effector cells that slowly convert over time. The longest-lived memory cells upregulate the transcription factor Tcf-1 (encoded by Tcf7) and bear similarities to the stem-like CD8s that are the targets of checkpoint inhibitor blockade. The transcriptional control within effector cells that re-establishes the long-lived memory program is unclear. We demonstrate that Runx3 transcriptional activity induced expression of cytotoxic effector molecules and promoted re-expression Tcf7 and CD62L. Runx3 induced memory cells that localized to secondary lymphoid organs, a key characteristic of long-lived central memory cells. This pleiotropy derived from distinct domains in Runx3. The activation domain directed the acquisition of both the cytotoxic effector program and the memory program, whereas its VWRPY domain regulated the conversion kinetic of effectors into memory cells. Furthermore, the inhibition domain delineated memory and exhaustion programs by direct repression of Tox, a gene that encodes an exhaustion-defining transcription factor. Thus, Runx3 coordinates both cytotoxic effector function and long-lived memory formation, while preventing terminal effector differentiation and exhaustion. These results suggest distinct Runx3 domains co-opt alternative chromatin regulators, which could potentially be targeted pharmacologically to manipulate CD8 T cell responses. Funding Sources NIAID P01 AI145815 to M. Pipkin; AHA 24PRE1191318 to D. Albao Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)