Runx3 drives a CD8 T cell tissue residency program that is absent in CD4 T cells.

Tissue-resident memory T cells (T cells) provide rapid and superior control of localized infections. While the transcription factor Runx3 is a critical regulator of CD8 T cell tissue residency, its expression is repressed in CD4 T cells. Here, we show that, as a direct consequence of this Runx3-deficiency, CD4 T cells lacked the transforming growth factor (TGF)-β-responsive transcriptional network that underpins the tissue residency of epithelial CD8 T cells. While CD4 T cell formation required Runx1, this, along with the modest expression of Runx3 in CD4 T cells, was insufficient to engage the TGF-β-driven residency program. Ectopic expression of Runx3 in CD4 T cells incited this TGF-β-transcriptional network to promote prolonged survival, decreased tissue egress, a microanatomical redistribution towards epithelial layers and enhanced effector functionality. Thus, our results reveal distinct programming of tissue residency in CD8 and CD4 T cell subsets that is attributable to divergent Runx3 activity.