The histone methyltransferase mixed-lineage-leukemia-1 drives T cell phenotype via notch signaling in diabetic tissue repair.

Abstract

Immune cell mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+T cells in normal or diabetic wound repair, however, the imbalance of CD4+TH17/Treg cells has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase MLL1 directly regulates the TH17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Further, we found that Notch receptor signaling regulates CD4+TH cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+T cells resulted in the loss of CD4+TH cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling were upregulated in wound CD4+TH cells, driving CD4+ T cells towards the TH17 cell phenotype. Treatment of diabetic wound CD4T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+TH17 cells and IL17A. This is the first study to identify the MLL1-mediated mechanisms responsible for regulating the TH17/Treg balance in normal and diabetic wounds and define the complex role of Notch signaling in CD4+T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+TH cells may decrease pathologic inflammation through regulation of CD4+T cell differentiation.