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Nature. 2017 Jun 1;546(7656):158-161. doi: 10.1038/nature22352. Epub 2017 May 24.

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

Author information

1
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
2
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
3
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York 10021, USA.
4
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK.
5
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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 S1P1 receptor (S1P1R) 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 S1P1R on T cells, and that the requirement for S1P1R 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.

PMID:
28538737
PMCID:
PMC5683179
DOI:
10.1038/nature22352
[Indexed for MEDLINE]
Free PMC Article

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