S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes
Dhaval Dixit, Victoria M. Hallisey, Ethan Y.S. Zhu, Martyna Okuniewska, Ken Cadwell, Jerry E. Chipuk, Jordan E. Axelrad, Susan R. Schwab
Dhaval Dixit, Victoria M. Hallisey, Ethan Y.S. Zhu, Martyna Okuniewska, Ken Cadwell, Jerry E. Chipuk, Jordan E. Axelrad, Susan R. Schwab
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Research Article Immunology

S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes

Abstract

Effective immunity requires a large, diverse naive 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 addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited 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 were required to prevent this proapoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naive T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.

Authors

Dhaval Dixit, Victoria M. Hallisey, Ethan Y.S. Zhu, Martyna Okuniewska, Ken Cadwell, Jerry E. Chipuk, Jordan E. Axelrad, Susan R. Schwab

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Figure 7

Loss of S1PR1 internalization contributes to apoptosis.

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Loss of S1PR1 internalization contributes to apoptosis. T cells were iso...
T cells were isolated from LNs of S1pr1Δ mice, activated in vitro with anti-CD3/CD28, and retrovirally transduced with vector encoding either IRES-GFP (empty vector), WT S1PR1-IRES-GFP, or ST10A S1PR1-IRES-GFP. Transduced T cells were cultured for 3 days in IL-7/IL-15 medium to generate predominantly CD8+ “central memory–like” T cells. These T cells were transferred into WT recipients, and 5 days later, transferred CD8+ T cells were analyzed. (A) Schematic of ST10A. (B) Experiment design. (C and D) Representative histogram and compilation of relative surface S1PR1 expression on cells in blood and LNs. Relative surface S1PR1 represents MFI on cells in 1 mouse divided by the mean MFI on WT S1PR1-transduced T cells in that experiment. (E) Absolute S1PR1 MFI values on the indicated cells. (F) Frequency of annexin V+ cells among CD8+ GFP+ T cells in LNs. (G) Relative MFI for BCL2 and p-JNK in CD8+ GFP+ T cells in LNs. Relative values represent expression in 1 mouse divided by the mean for WT S1PR1-transduced cells in that experiment. Compilation of 5 experiments, 5–6 per group. C–E, Student’s t test; F and G, 1-way ANOVA with multiple comparisons. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.