Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes

Maximilien Evrard, Erica Wynne-Jones, Changwei Peng, Yu Kato, Susan N. Christo, Raissa Fonseca, Simone L. Park, Thomas N. Burn, Maleika Osman, Sapna Devi, Jerold Chun, Scott N. Mueller, George Kannourakis, Stuart P. Berzins, Daniel G. Pellicci, William R. Heath, Stephen C. Jameson, Laura K. Mackay

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.

Original languageEnglish (US)
Article numbere20210116
JournalJournal of Experimental Medicine
Issue number1
StatePublished - Oct 22 2021

Bibliographical note

Funding Information:
This work was supported by a Howard Hughes Medical Institute and Bill and Melinda Gates Foundation International Research Scholarship OPP1175796 to L.K. Mackay and Australian Research Council grant DP200102753 to L.K. Mackay and M. Evrard. M. Evrard is supported by the University of Melbourne McKenzie Postdoctoral Fellowship. S.L. Park is supported by a National Health and Medical Research Council Emerging Leadership Investigator grant. D.G. Pellicci is supported by a Commonwealth Serum Laboratories Centenary Fellowship. L.K. Mackay is a senior medical research fellow supported by the Sylvia and Charles Viertel Charitable Foundation.

Publisher Copyright:
© 2021 Evrard et al.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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