Abstract
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.
Highlights
CD4+ T cells play a central role in primary alloresponses after solid organ transplantation (SOT) by providing effector cytokines and cognate help for cytotoxic CD8+ T lymphocytes and B-cell activation
As mucosa-associated lymphoid tissue lymphoma translocation gene 1 (Malt1)-deficiency was shown to protect against the development of experimental autoimmune encephalomyelitis (EAE) despite diminished Treg numbers [26, 27], we tested whether it could protect against graft rejection in a skin transplantation model
B6D2 donor skins were used as allografts for Malt1-ko, control Wt B6 recipients and Wt B6 mice that were treated with cyclosporine A (CsA) (Figure 1A)
Summary
CD4+ T cells play a central role in primary alloresponses after solid organ transplantation (SOT) by providing effector cytokines and cognate help for cytotoxic CD8+ T lymphocytes and B-cell activation. T-cell activation is regulated by a set of transcription factors belonging to the nuclear factor kappa-B (NF-κB) and nuclear factor of activated T cells (NFAT) families [4]. The ligation of the T-cell receptor (TCR) by cognate antigens leads to increased levels of intracellular calcium and activation of the calcium-dependent phosphatase enzyme calcineurin that dephosphorylates NFAT. Targeting Malt to Prevent Rejection of the gene encoding interleukin-2 (IL-2). By blocking this downstream TCR signaling, calcineurin inhibitors (CNI) prevent T-cell activation and downstream transcription of IL-2. Despite the success of CNI in preventing acute rejection they cannot fully control chronic immune activation leading to graft dysfunction [5]. Inhibition of the classical NF-κB signaling pathway could be considered as an immunosuppressive strategy
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