Sphingosine 1-phosphate receptor 1 inhibition induces a pro-apoptotic signaling cascade in T cells
Dixit, D.; Hallisey, V. M.; Zhu, E. Y. S.; Okuniewska, M.; Cadwell, K.; Chipuk, J. E.; Axelrad, J.; Schwab, S. R.
Show 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 address how S1P enables T cell survival, and the implications for patients treated with S1PR1 antagonists. Contrary to expectations, we found that S1PR1 limits 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 are 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 naive T cells limited B cell responses. Our findings highlight an unexpected effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggest both limitations and novel uses of this important class of drugs.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Integration of IL-2 and IL-4 Signals Coordinates Divergent Regulatory T cell Responses and Drives Therapeutic Efficacy 97%
- Kidins220 regulates the development of B cells bearing the {lambda} light chain 96%
- Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells 96%
Similar papers in this journal
- A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response 97%
- Single-Cell Multiomics Defines Tolerogenic Extrathymic Aire-Expressing Populations with Unique Homology to Thymic Epithelium 97%
- Invasion of spontaneous germinal centers by naive B cells is rapid and persistent 96%
Similar papers in this journal
- A20's Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis 97%
- Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function 97%
- Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues 96%
Similar papers in this journal
- T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response 98%
- TGF-β broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner 96%
- Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism 96%
Similar papers in this journal
- ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue 97%
- Cell-intrinsic functions of the transcription factor Bhlhe40 in activated B cells and T follicular helper cells restrain the germinal center reaction and prevent lymphomagenesis 96%
- Active Translation Control of CD4 T Cell Activation by Regulatory T Cells 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.