Sphingosine 1-phosphate maintains naïve T cell by regulating apoptotic signaling

Effective immunity requires a large, diverse naïve T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we address how S1P enables T cell survival, and the implications for patients treated with S1PR1 antagonists. Contrary to expectations, we found that S1PR1 limits apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization are required to prevent JNK overactivation and limit apoptosis. Findings in mice were recapitulated in ulcerative colitis patients treated with the drug ozanimod, and the loss of naïve T cells limited B cell responses. Our findings highlight an unexpected effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress. We analyzed gene expression difference between control naive CD4 T cells and naive CD4 T cells lacking S1P signaling (either from SPNS2-deficient mice or from S1PR1-deficient mice). For SPNS2: CD45.2 Spns2f/f Lyve1-Cre mice or CD45.2 littermate control mice were lethally irradiated and reconstituted with WT CD45 .1/.2 bone marrow. After reconstitution, naïve CD4 T cells were sorted by FACS and RNA-Seq was performed. For S1PR1: a 50:50 mixture of CD45.2 UBC-GFP:CD45.2 S1pr1f/f UBC-CreERT2 or CD45.2 UBC-GFP:CD45.2 S1pr1f/f littermate control bone marrow was transferred into lethally irradiated CD45.1/.2 WT mice. After reconstitution, mice were treated with tamoxifen. Four weeks after tamoxifen treatment, CD45.2 S1PR1-deficient or CD45.2 control naïve T cells were sorted and RNA-Seq was performed.