CD109 Restrains Activation of Cutaneous IL-17-Producing γδ T Cells by Commensal Microbiota

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. [Display omitted] •CD109 is a negative regulator of the cutaneous IL-23/IL-17 immune axis•Deletion of CD109 amplifies IL-17 production by skin γδ T cells•CD109 enforces skin barrier integrity and reactivity to commensal microbiota Zhang et al. demonstrate that CD109 acts in a skin-specific and cell-extrinsic manner to regulate interleukin (IL)-17 production by cutaneous γδ T cells. Genetic loss of CD109 results in spontaneous skin inflammation and an enhanced susceptibility to psoriasiform inflammation, a phenotype that can be reversed with topical application of antibiotics.