Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells

Cell-mediated immunity critically depends on the localization of lymphocytes at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells (T-RM cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of T-RM cells is unknown. We found that CD8(+) T-RM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P(1), a receptor for sphingosine 1-phosphate). Forced expression of S1P(1) prevented the establishment of T-RM cells. Cytokines that induced a T-RM cell phenotype (including transforming growth factor-beta (TGF-beta), interleukin 33 (IL-33) and tumor-necrosis factor) elicited downregulation of KLF2 expression in a pathway dependent on phosphatidylinositol-3-OH kinase (PI(3) K) and the kinase Akt, which suggested environmental regulation. Hence, regulation of KLF2 and S1P(1) provides a switch that dictates whether CD8(+) T cells commit to recirculating or tissue-resident memory populations.