IFN-γ signaling stimulates intestinal crypt hyperplasia in celiac disease

Celiac disease, an enteropathy driven by a maladaptive immune response to dietary gluten, is marked by increased proliferation in intestinal crypts, or crypt hyperplasia. However, it is unknown whether this phenomenon is a compensatory response to loss of villus epithelial cells or if it is driven by independent mechanisms. In this issue of the JCI, Stamnaes et al. demonstrated that in untreated celiac disease, crypt cells had increased expression of proteins involved in the IFN response, with decreased expression of fatty acid metabolism pathways. These expression patterns were recapitulated in mice treated with IFN-γ, but not mice with intestinal epithelial cell-specific knockout of the IFN-γ receptor. The findings suggest that crypt cells were reprogrammed directly by IFN-γ signaling, independent of changes to epithelial villi.