Journal
NATURE
Volume 546, Issue 7656, Pages 158-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature22352
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Funding
- National Institutes of Health (NIH) [R01 AI085166, AI123308]
- NIH [R01 CA206005, R01 HL089934, R37 AI43542, T32 AI100853]
- Tisch Cancer Institute Cancer Center Support Grant [P30 CA196521]
- American Cancer Society
- Leukemia & Lymphoma Society
- US National Science Foundation [1054964]
- NCI [R01 CA194547]
- Wellcome Trust
- Kennedy Trust for Rheumatology Research [PRF 100262Z/12/Z]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1054964] Funding Source: National Science Foundation
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Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide(1). Because the production of T cells declines with age, naive T cells must be long-lived(2). 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(3). 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(4).
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