S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes
Dhaval Dixit, … , Jordan E. Axelrad, Susan R. Schwab
Dhaval Dixit, … , Jordan E. Axelrad, Susan R. Schwab
Published January 9, 2024
Citation Information: J Clin Invest. 2024;134(4):e174984. https://doi.org/10.1172/JCI174984.
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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 4

BCL2 family proteins regulate S1PR1-dependent naive T cell survival.

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BCL2 family proteins regulate S1PR1-dependent naive T cell survival. (A ...
(A and B): (A) S1pr1Δ and littermate control lymphocytes labeled with CellTraceViolet or CellTraceYellow (dyes swapped between experiments) were cotransferred (1:1 for naive CD4+ T cells) i.v. into WT recipients. Twenty-four hours later, recipients were treated with ABT-199; 24 hours later, dye-labeled naive CD4+ T cells in LNs were enumerated. (B) Ratio of the number of naive CD4+ T cells from S1pr1Δ donor versus control donor recovered in indicated recipients. Compilation of 3 experiments, 5–6 per group. (C–E) Lymphocytes from LNs of S1pr1Δ or littermate control mice were treated with indicated concentrations of ABT-199 (D) or Fas ligand (E) ex vivo for 4 hours. Frequency of annexin V+ PI+ cells among naive CD4+ T cells measured by flow cytometry. Each point represents mean of 2 technical replicates, minus mean frequency of annexin V+ PI+ cells in 2 vehicle-treated technical replicates. Compilation of 3 experiments, 4 per group. (F and G): (F) Experiment design. (G) Relative BCL2, PUMA, and BAX expression in naive CD4+ T cells, shown as in Figure 3, B, D, and F. Compilation of 4 experiments, n = 5–8 per group. (H and I): (H) Bax–/– and WT littermate control lymphocytes labeled with CellTraceViolet or CellTraceYellow (dyes swapped between experiments) were cotransferred (1:1 for naive CD4+ T cells) i.v. into Spns2Δ mice and littermate controls; 21 days later, cells in skin-draining and mesenteric LNs were enumerated. (I) Ratio of WT/Bax–/– naive CD4+ T cells in indicated mice. Compilation of 3 experiments, 6–8 per group. (J) CellTraceViolet-labeled Bax–/– lymphocytes were transferred i.v. into Spns2fl/fl Lyve1-Cre mice or littermate controls; 21 days later, dye-labeled LN naive CD4+ T cells were analyzed by flow cytometry. Compilation of BCL2 and PUMA expression by Bax–/– naive T cells, as in Figure 3. Compilation of 3 experiments, 3–6 per group. B, D, E, and I, Student’s t test; G, 1-way ANOVA with multiple comparisons. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.