MEK inhibition prevents human skin graft rejection by promoting CD8+TCF1+ T cells over CD8 effector differentiated T cells.

While graft loss remains primarily attributed to rejection, the adverse effects of immunosuppressive therapies significantly contribute to patient morbidity and mortality. Therefore, it is imperative to develop treatments that both prevent alloimmune damage to the transplant and are well tolerated. MEK inhibition has recently been showed to be effective in controlling the alloimmune response in experimental mouse graft-versus-host disease, without abrogating anti-tumor nor anti-viral immunity. Here, we demonstrate that pharmacological MEK inhibition delays human skin graft rejection by human T cells in a preclinical humanized mouse model. Although similar graft infiltration was observed between treated and untreated animals, human epidermal cells were protected by the treatment. Single cell RNAseq analysis of the spleen immune cells revealed that MEK inhibition treatment inhibits CD8 T cell development to an effector phenotype and promotes the accumulation of CD8+TCF1+ stem-like cells. Furthermore, analysis of the CD4 cells showed that MEK inhibition improved CD4 T cell recovery by preserving IL7R expression on CD4 T cells and favored CD4 T cells engagement in the Th1 lineage rather than the Tfh lineage. These findings suggest that MEK inhibition could be an innovative approach to combining allogeneic immune response control and tissue protection after transplantation. To investigate the role of MEK inhibitors on graft survival we used a humanised mouse model in which human skin is transplanted and then infused with human PBMCs from third donor enabling gradual reconstitution and subsequent graft rejection. Single cell RNAseq experiment was performed on the mouse spleen treated or not with MEK inhibitors. --------------------- HTO barcode sequence hashtagged sample TotalSeq-C0251 anti-human Hashtag 1 GTCAACTCTTTAGCG 3790-sham TotalSeq-C0252 anti-human Hashtag 2 TGATGGCCTATTGGG 3798-tra TotalSeq™-C0253 anti-human Hashtag 3 TTCCGCCTCTCTTTG 3906-sham TotalSeq™-C0254 anti-human Hashtag 4 AGTAAGTTCAGCGTA 3907-tra