1. Academic Validation
  2. S1PR1 inhibition induces pro-apoptotic signaling in T cells and limits humoral responses within lymph nodes

S1PR1 inhibition induces pro-apoptotic signaling in T cells and limits humoral responses within lymph nodes

  • J Clin Invest. 2024 Jan 9:e174984. doi: 10.1172/JCI174984.
Dhaval Dixit 1 Victoria M Hallisey 1 Ethan Ys Zhu 1 Martyna Okuniewska 1 Ken Cadwell 2 Jerry E Chipuk 3 Jordan E Axelrad 4 Susan R Schwab 1
Affiliations

Affiliations

  • 1 Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, United States of America.
  • 2 Department of Medicine and Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America.
  • 3 Department of Oncological Sciences, Department of Dermatology, and Tisch Ca, Icahn School of Medicine at Mount Sinai, New York, United States of America.
  • 4 Division of Gastroenterology, Department of Medicine, New York University Grossman School of Medicine, New York, United States of America.
Abstract

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 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 pro-apoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 Antagonist ozanimod, and the loss of naïve 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.

Keywords

Adaptive immunity; Apoptosis; Cell migration/adhesion; Immunology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13319
    99.67%, JNK Inhibitor
    JNK