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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anion Transport Proteins / metabolism
  • Cell Movement
  • Cell Survival
  • Endothelial Cells / metabolism*
  • Female
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphoid Tissue / cytology*
  • Lymphoid Tissue / immunology
  • Lysophospholipids / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Peyer's Patches / cytology
  • Peyer's Patches / immunology
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology

Substances

  • Anion Transport Proteins
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • Spns2 protein, mouse
  • sphingosine 1-phosphate
  • Sphingosine