Conditional PDK1 ablation promotes epidermal and T cell-mediated dysfunctions leading to inflammatory skin disease

Phosphoinositide dependent kinase-1 (PDK1) is a key signaling molecule downstream of the phosphatidylinositol 3-kinase (PI-3 kinase) pathway and is a master regulator of multiple kinases in cells of epithelial and hematopoietic lineages. The physiological role of PDK1 in regulating skin and immune homeostasis is not known. Here we developed a mouse model in which PDK1 is conditionally ablated in activated CD4 T cells, regulatory T cells and mature keratinocytes, through OX40-Cre recombinase expression. The resultant mice (PDK1-CKO) spontaneously developed severe dermatitis, skin fibrosis and systemic Th2 immunity, succumbing by 11 weeks of age. Through a series of T cell transfers, bone marrow reconstitutions and crossing to lymphocyte-deficient backgrounds, we demonstrate that ablation of PDK1 in keratinocytes is the major driver of disease pathogenesis. PDK1-deficient keratinocytes exhibit intrinsic defects in expression of key structural proteins including cytokeratin-10 and loricrin, resulting in increased keratinocyte turnover, which in turn, triggers inflammation, T cell recruitment and immune-mediated destruction. Our results reveal PDK1 as a central regulator of keratinocyte homeostasis which prevents skin immune infiltration and inflammation.