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

Tissue-resident memory T cells (T_RM 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_RM cells lacked the transforming growth factor (TGF)-β-responsive transcriptional network that underpins the tissue residency of epithelial CD8⁺ T_RM cells. While CD4⁺ T_RM cell formation required Runx1, this, along with the modest expression of Runx3 in CD4⁺ T_RM 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_RM cell subsets that is attributable to divergent Runx3 activity.