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S1P: the elixir of life for naive T cells

Cellular & Molecular Immunology volume 15, pages 657–659 (2018)Cite this article

During their life, T cells are constantly circulating throughout the body. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, triggers T cell egress from the thymus and secondary lymphoid organs (SLO) into the lymph and the blood. This phenomenon is dependent on the S1P gradient between lymphoid organs (including thymus and SLO) and the lymphatic and blood vessels, which exhibit low, intermediate and high S1P levels, respectively. T cells follow the S1P gradient via the engagement of the G-protein-coupled receptor S1P receptor 1 (S1P1) expressed on T cells.1 S1P production is regulated by various sphingolipid-metabolizing enzymes. The sphingosine kinases 1 and 2 (SKs), encoded by Sphk1 and Sphk2, phosphorylate the sphingosine (Sph) into S1P. Conversely, S1P can be dephosphorylated to Sph by S1P phosphatases 1 and 2, encoded by Sgpp1 and Sgpp2. Alternatively, S1P can be irreversibly degraded by the S1P Lyase (SPL), encoded by Sgpl1, into phosphoethanolamine and hexadecenal. The secretion of S1P was described to involve two transporters, the ATP-binding cassette (ABC) transporter, in a non-specific manner, and the recently identified specific transporter Spinster 2 (SPNS2), encoded by the Spns2 gene.2 As a result, Spns2-deficient mice exhibit decreased concentrations of S1P into the lymph but not blood.3 In a recent study, Mendoza et al. reported that S1P, which is secreted by lymphatic endothelial cells via SPNS2, favors naive T-cell survival by maintaining their mitochondrial content in an S1P1-dependent manner.4 Herein, we discuss the main findings and pathophysiological implications of the latter study as regard to the state of the art.

Maturation of naive T cells occurs in the thymus and rises to ~108 different T-cell receptors (TCR). Newly differentiated single positive CD4 and CD8 thymocytes, which express S1P1 at high levels, migrate from the thymus to the blood stream following the S1P gradient.5 In the blood, high concentrations of S1P induce the internalization of S1P1 allowing for potential relocation of T cells into SLO or tissues. Within SLO, naive T cells patrol until they encounter their specific peptide presented by an antigen-presenting cell (APC). During T cell activation, S1P1 is trapped inside the cells through its interaction with the very early activation antigen marker CD69. This induces T-cell arrest into the lymph node to allow for proliferation and differentiation of antigen specific T cells. S1P1 is then re-expressed by both effector and central memory T cells and exit the lymph node.6 Unactivated naive T cells, which travel through the lymph nodes, do not down-regulate S1P1 at their cell surface and go back directly to the circulation through the sensing of S1P gradient. Of note, transgenic mice with a targeted deletion of Spns2 in endothelial cells exhibited (i) low S1P levels in the lymph and (ii) reduced T-cell content in the blood, spleen and lymph nodes, further arguing for the key role S1P plays in T-cell trafficking.

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Authors and Affiliations

  1. INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31037, Toulouse, France

    Michaël Pérès, Anne Montfort, Nathalie Andrieu-Abadie, Céline Colacios & Bruno Ségui

  2. Faculté de pharmacie, Université Toulouse III Paul-Sabatier, 31062, Toulouse, France

    Michaël Pérès, Céline Colacios & Bruno Ségui

  3. Laboratoire d’hématologie, CHU de Toulouse, 31059, Toulouse, France

    Michaël Pérès

  4. Equipe Labellisée Ligue Contre Le Cancer, 31037, Toulouse, France

    Michaël Pérès, Anne Montfort, Nathalie Andrieu-Abadie, Céline Colacios & Bruno Ségui

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Pérès, M., Montfort, A., Andrieu-Abadie, N. et al. S1P: the elixir of life for naive T cells. Cell Mol Immunol 15, 657–659 (2018). https://doi.org/10.1038/cmi.2017.110

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