Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 3

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

  • Text
  • PDF
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

×

Figure 9

Prolonged FTY720 treatment impairs germinal center responses.

Options: View larger image (or click on image) Download as PowerPoint
Prolonged FTY720 treatment impairs germinal center responses.
(A–D): (A)...
(A–D): (A) WT mice were divided into 3 groups: “Long FTY,” 1 mg/kg FTY720 every other day for 3 weeks (starting day –21); “Vehicle,” vehicle for 3 weeks (starting day –21); and “Short FTY,” untreated until day –1, when they received 1 mg/kg FTY720. On day 0, all mice received 108 sheep red blood cells (SRBCs) subcutaneously. FTY720 (long and short groups) or vehicle (vehicle group) treatment continued until day 8, when draining LNs were analyzed. (B) Representative plots of GCB cells (Fas+CD38–), gated on B220+ B cells. Numbers represent percentage GC of total B cells. (C and D) Number of GCB (C) or Tfh (D) cells in draining LNs. Compilation of 3 experiments, 5–6 per group. (E–G): (E) Three groups of WT mice were treated with FTY720 for 3 weeks. One group (Long FTY + polyclonal T cells) received CD4+ and CD8+ naive T cells from FTY720-treated WT mice (donor mice initiated FTY720 at the same time as recipient groups), either once (day –1: black-outlined circles) or 3 times (days –15, –8, and –1: filled circles). The second group received OVA-specific CD4+ and CD8+ T cells from FTY720-treated OT-I and OT-II transgenic mice (donor mice initiated FTY720 at the same time as recipient groups) 3 times (days –15, –8, and –1: filled circles); the OT-I/OT-II ratio matched the CD8+/CD4+ T cell ratio in the polyclonal transfer. One group received FTY720 at day –1 (Short FTY). On day 0, all mice received 108 SRBCs subcutaneously. FTY720 treatment continued in all groups until day 8, when draining LNs were analyzed. (F and G) Number of GCB cells (F) and Tfh cells (G) in draining LNs. Four experiments, 5–10 per group. C and D, 1-way ANOVA with multiple comparisons; F and G, Brown-Forsythe and Welch’s ANOVA test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 5 X users
13 readers on Mendeley
See more details