Get me out of here: Sphingosine 1‐phosphate signaling and T cell exit from tissues during an immune response

Abstract

SummaryDuring an immune response, the duration of T cell residence in lymphoid and non‐lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1‐phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G‐protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

“…5 ). S1PR1 is abundantly expressed in all cell types, including large variety of immune cells [ 168 , 169 ], indicating the high importance of this receptor for the regulation of vital cell functions. The receptor signals via G i/o heterotrimeric proteins which may inhibit adenylyl cyclase and activate potassium channels [ 170 ].…”

“…It is common to observe the co-expression of different S1P receptors, especially presence of S1PR1 and S1PR3 within one cell type which may indicate cooperation of signaling among the receptors [ 174 ]. In comparison to S1PR1 and S1PR3 effects, S1PR4 was found to be growth-inhibitory in some immune cells [ 175 ], while its role in the lymphocyte trafficking and expansion was extensively discussed [ 169 ]. The receptor may regulate the cytotoxicity of T cells towards cancerous tissues [ 176 ], although downstream signaling pathways of S1PR4 remain largely unclear.…”

“…G i/o and G 12/13 were shown to transmit S1PR4 and S1PR5 signals in normal and malignant cells [ 178 ]. The expression of S1PRs in both cancer and immune cells represents a debatable phenomenon which was recently reviewed [ 169 ]. To complicate the problem, the level of S1PR expression may vary during morphogenesis, cell growth and differentiation [ 153 ].…”

“…In majority of these cells, S1P secretion is mediated by ATP-binding cassette transporters (ABC-transporter) [ 180 , 184 ]. S1P gradient, the difference between the intra- and extra-cellular concentrations of S1P, modulates S1PRs expression and represents a novel factor in the regulation of S1P signaling in the immune system and circulation [ 169 , 184 ].

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Lipid mediators in the regulation of innate and adaptive immunity

“…From our initial understanding almost two decades ago that S1PR1 was essential for thymocytes to exit the thymus and join the peripheral pool of mature antigen‐responsive T cells, there has been great interest in better understanding how the sphingosine‐1‐phosphate lysophospholipid and its cognate S1P GPCRs orchestrate immune cell trafficking and migration in health and disease. In their review, Hallisey and Schwab 11 provide an update on key areas in S1P biology as they relate to T cell trafficking in and out of lymphoid and non‐lymphoid organs not only in homeostasis but particularly during inflammatory settings. This review includes a thoughtful consideration on the implications of altered T cell trafficking in lymphoid organs for T cell immunity.…”