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

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

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.

Highlights

Effective immune protection relies on the generation of longlived memory T cells
We began by comparing established transcriptomic profiles (Mackay et al, 2013) of antigen-specific CD69+CD103+CD8+ TRM cells isolated from the skin, lung, and small intestine after HSV-KOS, influenza virus (WSN.gB), or acute lymphocytic choriomeningitis virus (LCMV-Armstrong) infection, respectively, with their circulating effector memory T cell (TEM cell) and central memory T cell (TCM cell) counterparts
Whereas S1pr2, S1pr3, and S1pr4 were expressed by resident and circulating T cell populations, S1pr1 and S1pr5 were selectively downregulated in TRM cells across all three tissues (Fig. 1 A)

Summary

Introduction

Effective immune protection relies on the generation of longlived memory T cells. During a typical immune response, naive T cells surveying lymphoid organs are activated by cognate antigen and differentiate into short-lived effector cells (SLECs) or long-lived memory T cells (Kaech and Cui, 2012; Omilusik and Goldrath, 2019). Nonrecirculating tissue-resident memory T cells (TRM cells) reside in a wide range of organs, such as the skin, gut, and lung There, they form a defensive barrier, providing potent immune protection against a plethora of infections and cancer (Masopust and Soerens, 2019; Park et al, 2019; Szabo et al, 2019). After effector T cells enter inflamed tissues, multiple factors determine whether TRM cell precursors “stay” to receive local signals that promote TRM cell differentiation, or “go” and return to the circulation (Mackay et al, 2013) These decisions fundamentally shape the course of the immune response and the magnitude of protective immunity that ensues, yet the signals orchestrating these processes are not yet fully understood

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