Suppression of epithelial proliferation and tumorigenesis by IgA

Immunoglobulin A (IgA) is the most abundant antibody isotype produced by mammals, playing a specialised role in mucosal homeostasis 1 . IgA is constantly secreted into the intestinal lumen and binds commensal microbiota to regulate their colonisation and function 2,3 , with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities 4–8 . Using genetically and environmentally controlled mice, here we show that multiple animal models of IgA deficiency result in increased susceptibility to multiple models of endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to reduce steady-state proliferation and protect mice from tumours; however, this function was due to the antibody structure rather than binding specificity. In a reductionist culture system, IgA directly suppresses epithelial growth. Co-immunoprecipitation mass spectrometry and targeted CRISPR screening identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 tune the normal cycling of absorptive colonocyte progenitors. In mice, deletion of the transmembrane and cytoplasmic signalling portions of DMBT1 was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.