title: Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells.
abstract: 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 S1P1, a receptor for sphingosine 1-phosphate). Forced expression of S1P1 prevented the establishment of T(RM) cells. Cytokines that induced a T(RM) 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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Cara N
authors.initials: CN
authors.lastname: Skon
authors.forename: June-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Anderson
authors.forename: David
authors.initials: D
authors.lastname: Masopust
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Jameson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000081025:Sphingosine-1-Phosphate Receptors; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000067596:Interleukin-33; D007378:Interleukins; D051741:Kruppel-Like Transcription Factors; D037181:Lectins, C-Type; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C506535:Il33 protein, mouse; C498314:Klf2 protein, mouse; C556330:S1pr1 protein, mouse