The chemoattractant sphingosine 1-phosphate (S1P) promotes T cell egress from lymph nodes and is important for T cell recirculation through secondary lymph nodes. Reporting in Nature, Mendoza et al. describe a previously unappreciated role for S1P and its transporter SPNS2 in supporting the survival of naive T cells.

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Previous work had shown that mice deficient in SPNS2 (which transports S1P to the lymph) have a markedly reduced number of naive T cells in their secondary lymphoid organs. This was thought to reflect defective export of T cells from the thymus. To test this, Mendoza et al. generated Spns2Δ mice, in which SPNS2 is not expressed by lymphatic endothelial cells but is still expressed by the blood vessel endothelial cells that regulate T cell egress from the thymus. Despite T cells egressing normally from the thymus, naive T cell numbers were still markedly reduced in the lymph nodes and spleens of the Spns2Δ mice. Naive T cell numbers were not increased in other tissues of Spns2Δ mice, and these cells did not appear to undergo spontaneous activation or have reduced levels of homeostatic proliferation, suggesting that their survival may be impaired.

In support of this idea, naive CD4+ T cells from the spleens and lymph nodes of Spns2Δ mice showed increased rates of cell death and apoptosis compared with controls. Increased rates of naive CD4+ T cell death were also seen in Spns2Δ mice reconstituted with wild-type bone marrow. When the authors co-transferred T cells from wild-type mice or BCL2-transgenic mice (which are resistant to the mitochondrial pathway of apoptosis) into wild-type or Spns2Δ mice, equal numbers of each T cell population were detected in the lymph nodes of wild-type recipients, but more BCL2-transgenic T cells were recovered from the lymph nodes of Spns2Δ recipients. Therefore, naive T cells seem to be more prone to apoptosis when lymphatic endothelial cells lack functional SPNS2.

S1P promotes naive T cell survival by supporting mitochondrial function

The authors tested whether restoring S1P exposure without restoring T cell recirculation in Spns2Δ mice could prevent the loss of naive T cells. Indeed, experiments using an inhibitor of the S1P-degrading enzyme S1P lyase suggested that S1P supports T cell survival independently of its role in promoting egress. They next generated S1pr1Δ mice, in which the S1P receptor S1PR1 can be inducibly deleted. Experiments using these animals implicated a cell-intrinsic role for S1PR1 signalling in mediating naive T cell survival — naive T cells from S1pr1Δ mice show downregulation of transcripts associated with cell survival and upregulation of transcripts associated with cell death.

S1PR1 signalling did not seem to support T cell survival by regulating their access to IL-7 and self-peptide–MHC complexes in the lymph node. Instead, T cells from S1pr1Δ mice showed signs of mitochondrial dysfunction, including a 40% reduction in both total and functional mitochondria. Furthermore, S1pr1Δ T cells had lower oxygen consumption rates than controls, and activated S1pr1Δ T cells showed lower levels of proliferation when relying on oxidative phosphorylation, but proliferated similarly to controls when able to use glycolysis.

These findings show that S1P promotes naive T cell survival by supporting mitochondrial function. The authors propose that given the high energy costs of constant recirculation, it is efficient for naive T cells to use the same signals to support recirculation and mitochondrial function.