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

Jameson and colleagues show that the establishment of resident memory CD8+ T cells in nonlymphoid tissues requires transcriptional downregulation of the trafficking molecule S1P1, mediated by induced loss of the transcription factor KLF2. 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 (TRM cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of TRM cells is unknown. We found that CD8+ TRM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P1, a receptor for sphingosine 1-phosphate). Forced expression of S1P1 prevented the establishment of TRM cells. Cytokines that induced a TRM cell phenotype (including transforming growth factor-β (TGF-β), 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 S1P1 provides a switch that dictates whether CD8+ T cells commit to recirculating or tissue-resident memory populations.