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 (T_RM) cell formation in non-lymphoid tissues after mucosal infections. We find that Tcf1 is progressively decreased during lung T_RM cell formation. Abrogation of transforming growth factor β (TGF-β) 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 T_RM 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-β-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.

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