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

Cara N. Skon, June Yong Lee, Kristin G. Anderson, David Masopust, Kristin A. Hogquist, Stephen C. Jameson

Research output: Contribution to journalArticlepeer-review

569 Scopus citations

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 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-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 S1P 1 provides a switch that dictates whether CD8 + T cells commit to recirculating or tissue-resident memory populations.

Original languageEnglish (US)
Pages (from-to)1285-1293
Number of pages9
JournalNature immunology
Volume14
Issue number12
DOIs
StatePublished - Dec 2013

Bibliographical note

Funding Information:
We thank J. Cyster (University of California, San Francisco) for the vector MSCV-S1PR1-hCD4; J. Chen (Massachusetts Institute of Technology) for the retroviral vector MSCV-IRES-Thy1.1 (MiT); K. Walkowiak and J. Schenkel for input on parabiosis; L. Mackay and D. Kaplan for advice on DNFB studies; and the Jamequist laboratory for intellectual support. Supported by the US National Institutes of Health (R37 AI38903 to S.C.J.; R37 AI39560 to K.A.H.; T32 AI07313 to C.N.S.; and T90 DE022732 to K.G.A.).

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