Lymphatic endothelial S1P promotes mitochondrial function and survival of naïve T cells
Dhaval Dixit1, Alejandra Mendoza1, Victoria Fang1, Cynthia Chen1, Madhavika Serasinghe2, Akanksha Verma3, James Muller1, V. Sai Chaluvadi1, Michael L. Dustin1, Timothy Hla4, Olivier Elemento3, Jerry E. Chipuk2 & Susan R. Schwab1 1Skirball Institute of Biomolecular Medicine, New York University School of Medicine, USA; 2Icahn School of Medicine at Mount Sinai, USA; 3Weill Cornell Medical College, USA; 4Harvard Medical School, USA
An effective immune response requires a large and diverse repertoire of naïve T cells that circulate throughout the body sampling antigen. It is still poorly understood how such a long-lived migratory cell persists over time. Sphingosine 1-phosphate (S1P) is a lipid chemoattractant that regulates T cell circulation. Using S1P receptor 1 (S1PR1), T cells follow S1P concentration gradients to exit tissues into blood or lymph. Here, we report a novel role for S1P in maintaining the survival of naïve T cells. Lymphatic endothelial cells support naïve T cell survival by secreting S1P through the transporter SPNS2. This secreted S1P signals through S1PR1 on T cells to prevent apoptosis and the survival defect is independent of S1P and S1PR1's role in exit. S1P signaling maintains mitochondrial content and function of naïve T cells. Cells deficient in S1PR1 have increased ubiquitination of their mitochondria, suggestive of increased mitophagy in the absence of S1P. Thus, S1P signaling acts not only as a directional cue, but also to provide energy for survival during migration. Further experiments will elucidate the mitochondrial dysfunction and the pathway between S1PR1 signaling and mitochondrial regulation. The S1P signaling pathway is being therapeutically targeted to manipulate autoreactive T cell migration and this works suggests that inhibiting this mechanism may also affect survival or metabolic function of T cells in autoimmunity.
Credits: None available.
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