Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_67419B803F44
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts.
Périodique
Frontiers in immunology
Auteur(s)
Govender L., Mikulic J., Wyss J.C., Gaide O., Thome M., Golshayan D.
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Statut éditorial
Publié
Date de publication
2020
Peer-reviewed
Oui
Volume
11
Pages
576651
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
Strategies targeting T cells are the cornerstone of immunosuppression after solid organ transplantation. The transcription factor NF-κB is a key regulator of downstream T-cell activation and induction of inflammatory mediators; its full activation via antigen receptor engagement requires both the scaffold and the protease activity of the paracaspase Malt1. Experimental studies have highlighted that Malt1-deficient mice were resistant to experimental autoimmune encephalomyelitis, although they lacked peripheral regulatory T cells (Treg). Here, we compared targeting Malt1 versus using calcineurin inhibitors as immunosuppression in a stringent experimental transplantation model. We found that Malt1-deficiency impaired Th1-mediated alloresponses in vitro and in vivo and significantly prolonged MHC-mismatched skin allograft survival, compared to cyclosporine. However, it paradoxically enhanced Th17 differentiation in the transplantation setting. Interestingly, more selective inhibition of Malt1 protease activity in wild-type mouse and human peripheral T cells in vitro led to attenuation of alloreactive Th1 cells, while preserving preexisting Treg in the peripheral T-cell pool, and without promoting Th17 differentiation. Thus, there is a place for further investigation of the role of Malt1 signaling in the setting of transplantation.
Mots-clé
NF-kB, Th17 cells, calcineurin inhibitors, paracaspase, regulatory T cells, transplantation
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/10/2020 15:56
Dernière modification de la notice
30/04/2021 7:11
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