LAUSR

demonstrated that the absence of IRF4 leads to deficient immune responses in infection and autoimmune disease. In the study from Wu and co-workers, IRF4 was investigated in the context of transplantation. In a mouse model of heterotopic heart transplantation, IRF4 was found to be overexpressed in graft-infiltrating T cells. Use of T cellspecific IRF4 knockouts as recipient mice led to long-term survival of heart allografts with minimal ensuing damage to the transplants and an associated impairment in cytokine production. In these IRF4-deficient CD4+ T cells, the expression of PD-1, a molecule associated with T cell dysfunction, was found to increase with in vitro stimulation. Notably, IRF4 was shown to directly repress the expression of PD-1. In an important therapeutic advance, the authors then investigated the ability of the IRF4 inhibitor trametinib to target CD4+ Tcells. Treatment with this inhibitor promoted transplant survival, increasing median survival time of the mouse heart allografts by approximately 6 days. These experiments therefore demonstrate an important new therapeutic target in transplantation. PD-1 blockade, for example, with pembrolizumab, is increasingly used as a cancer therapy in various metastatic tumors. However, an adverse effect of this type of checkpoint inhibition in transplantation is the risk of triggering rejection. Although treatment in this subgroup of patients is a fine balance between immune activation and suppression, the direct inhibition of IRF4 is of interest as a therapeutic approach to treat rejection precipitated by PD-1 blockade. Further investigation of the effects of trametinib in transplantation is warranted.