Epithelial CD74 regulates intestinal barrier homeostasis

CD74, originally identified as the invariant chain of MHC class II, also functions as a receptor for macrophage migration inhibitory factor (MIF). Although CD74 is expressed in various non-lymphoid cells, including epithelial cells across multiple organs, the regulation and functional significance of its expression in these tissues remain poorly understood. Here, we show that CD74 is constitutively expressed in small intestinal epithelial cells, particularly within stem and transit-amplifying compartments, and that its expression is influenced by microbiota and IFN-γ signaling. Conditional deletion of CD74 in IECs (CD74 ΔIEC mice) resulted in increased intestinal permeability under steady-state conditions, which was consistent with reduced expression of the tight junction protein ZO-1. While the numbers of intestinal stem cells and Paneth cells remained unchanged, CD74-deficient mice also exhibited elongation of the small intestine and enhanced crypt cell proliferation. Single-cell RNA sequencing revealed enrichment of mitochondrial pathways in CD74-deficient IECs. Consistent with these findings, CD74-deficient IECs exhibited increased mitochondrial content and altered mitochondrial membrane potential. Organoid cultures further showed accelerated growth and increased proliferation in the absence of CD74. Together, these findings suggest that CD74 contributes to intestinal epithelial homeostasis by limiting epithelial proliferation and supporting tight junction integrity, thereby helping to maintain barrier function under steady-state conditions.