TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention.

Stem-like CD8+ T cells sustain the antigen-specific CD8+ T cell response during chronic antigen exposure. However, the signals that control the maintenance and differentiation of these cells are largely unknown. Here, we demonstrated that TGF-β was essential for the optimal maintenance of these cells and inhibited their differentiation into migratory effectors during chronic viral infection. Mechanistically, stem-like CD8+ T cells carried a unique expression pattern of α4 integrins (i.e., α4β1hi and α4β7lo) controlled by TGF-β. In the absence of TGF-β signaling, greatly enhanced expression of migration-related markers, including altered expression of α4 integrins, led to enhanced egress of stem-like CD8+ T cells into circulation accompanied by further differentiation into transitional states. Blocking α4 integrin significantly promoted their lymphoid tissue retention and therefore partially rescued the defective maintenance of Tcf-1+ subset in the absence of TGF-β signaling. Thus, TGF-β promotes the maintenance and inhibits the further differentiation of stem-like T cells at least partially via enforcing their lymphoid tissue residency.