Abstract
Interleukin-17-producing γδ T (γδ17) cells play a central role in protective and pathogenic immune responses. However, the tissue-specific mechanisms that control the activation of these innate lymphocytes are not known. Here, we demonstrate that CD109, a glycosylphosphatidylinositol (GPI)-anchored protein highly expressed by keratinocytes, is an important regulator of skin homeostasis and γδ17 cell activation. Genetic deletion of CD109 results in spontaneous epidermal hyperplasia, aberrant accumulation of dermal-derived γδ17 cells, and enhanced susceptibility to psoriasiform inflammation. In this context, γδ17 activation requires interleukin (IL)-23 signals and is reversed by transient depletion of the skin microbiota. Mechanistically, CD109 restrains γδ17 cell activation in a cell-extrinsic manner by fortifying skin barrier integrity. Collectively, our data provide insight into the regulation of the skin IL-23/IL-17 immune axis and how homeostasis is maintained at this important barrier site.