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

Cell-mediated immunity critically depends on lymphocyte localization at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells; T(RM)) are embedded in non-lymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for T(RM) establishment is unknown. We report that CD8(+) T(RM) cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (encoding sphingosine 1-phosphate receptor 1). Forced S1PR1 expression prevented establishment of T(RM). Cytokines inducing T(RM) phenotype (including TGF-β, IL-33 and TNF) provoked KLF2 downregulation in a phosphatidylinositol-3-OH kinase (PI(3)K)–Akt-dependent pathway, suggesting environmental regulation. Hence KLF2 and S1PR1 regulation provides a switch, dictating whether CD8(+) T cells commit to the recirculating or tissue resident memory populations.