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S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes.
Dixit, Dhaval; Hallisey, Victoria M; Zhu, Ethan Ys; Okuniewska, Martyna; Cadwell, Ken; Chipuk, Jerry E; Axelrad, Jordan E; Schwab, Susan R.
Affiliation
  • Dixit D; Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, New York, USA.
  • Hallisey VM; Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, New York, USA.
  • Zhu EY; Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, New York, USA.
  • Okuniewska M; Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, New York, USA.
  • Cadwell K; Department of Medicine and Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
  • Chipuk JE; Department of Oncological Sciences, Department of Dermatology, and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Axelrad JE; Division of Gastroenterology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
  • Schwab SR; Departments of Cell Biology and Pathology, New York University Grossman School of Medicine, New York, New York, USA.
J Clin Invest ; 134(4)2024 Jan 09.
Article in En | MEDLINE | ID: mdl-38194271
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / Lymph Nodes Limits: Animals / Humans Language: En Journal: J Clin Invest Year: 2024 Type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / Lymph Nodes Limits: Animals / Humans Language: En Journal: J Clin Invest Year: 2024 Type: Article Affiliation country: United States