Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8⁺ T cells

The networks of transcription factors (TFs) that control intestinal-resident memory CD8⁺ T (T_RM) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in T_RM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8⁺ T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal T_RM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b circulating precursors, with no major alterations in their programs. Bcl11b T_RM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7, and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8⁺ T_RM cell differentiation. Deregulation of T_RM programs translated into a poor recall response despite T_RM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b^-/- T_RM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.