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. Mackay and colleagues show that distinct programs of tissue residency are induced in CD8 + and CD4 + T RM cell subsets, a difference attributable to the activity of the transcription factor Runx3.