Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells

Alejandra Mendoza, Victoria Fang, Cynthia Chen, Madhavika Serasinghe, Akanksha Verma, James Muller, V. Sai Chaluvadi, Michael L. Dustin, Timothy Hla, Olivier Elemento, Jerry E. Chipuk, Susan R. Schwab

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

Abstract

Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P 1 receptor (S1P 1 R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P 1 R on T cells, and that the requirement for S1P 1 R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

Original languageEnglish
Pages (from-to)158-161
Number of pages4
JournalNature
Volume546
Issue number7656
DOIs
StatePublished - 1 Jun 2017

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