Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.576651
Keywords
transplantation; paracaspase; NF-kB; calcineurin inhibitors; regulatory T cells; Th17 cells
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Funding
- Swiss National Science Foundation
- Fondation Pierre Mercier pour La Science
- Fondation Medi-CAL Futur
- Fondation Lausannoise pour la Transplantation d'Organes
- Leenaards Foundation
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Strategies targeting T cells are the cornerstone of immunosuppression after solid organ transplantation. The transcription factor NF-kappa B 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 alloresponsesin vitroandin vivoand 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 cellsin vitroled 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.
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