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

J Exp Med. 2022 Jan 3;219(1):e20210116. doi: 10.1084/jem.20210116.

Maximilien Evrard ¹, Erica Wynne-Jones ¹, Changwei Peng ² ³, Yu Kato ¹ ⁴, Susan N Christo ¹, Raissa Fonseca ¹, Simone L Park ¹, Thomas N Burn ¹, Maleika Osman ¹, Sapna Devi ¹, Jerold Chun ⁵, Scott N Mueller ¹, George Kannourakis ⁶, Stuart P Berzins ¹ ⁶, Daniel G Pellicci ¹ ⁴ ⁷ ⁸, William R Heath ¹ ⁴, Stephen C Jameson ² ³, Laura K Mackay ¹ ⁴

Affiliations

1 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
2 Center for Immunology, University of Minnesota Medical School, Minneapolis, MN.
3 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
4 The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.
5 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
6 Federation University Australia and Fiona Elsey Cancer Research Institute, Ballarat, Victoria, Australia.
7 Cellular Immunology Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
8 Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.

PMID: 34677611 DOI: 10.1084/jem.20210116

Abstract

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.

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