T Cell Factor 1 Suppresses CD103+Lung Tissue-Resident Memory T Cell Development

T cell factor 1 (Tcf1) promotes the central memory CD8(+) T (T-CM) cell differentiation and stemness in lymphoid tissues after systemic infections. It remains unclear whether Tcf1 regulates the CD103(high) tissue-resident memory CD8(+) T (TRM) cell formation in non-lymphoid tissues after mucosal infections. We find that Tcf1 is progressively decreased during lung TRM cell formation. Abrogation of transforming growth factor beta (TGF-beta) signaling is associated with a loss of CD103(+) and reciprocal gain of Tcf1(+) cells among T-RM precursors in vivo. T-cell-specific ablation of Tcf7 enhances CD103 protein expression in TRM cells and precursors and increases T-RM cell numbers after primary and secondary infections. Tcf1 directly binds to the Itgae (encoding CD103) locus and partly inhibits TGF-beta-induced CD103 expression. Our study suggests that memory T cell tissue residency and homeostatic proliferation are reciprocally regulated by Tcf1. Tcf1 may play either immunosupportive or immunosuppressive roles in CD8(+) T cells, depending on systemic or mucosal infections.