Immunoglobulin A controls intestinal virus colonization to preserve immune homeostasis

Abstract

Immunoglobulin A (IgA) is the predominant immunoglobulin isotype in mammals, primarily secreted at type I mucosal surfaces. Despite its abundance, the precise role of secretory IgA in the intestinal lumen, where it coats a diverse array of commensal microbiota, has remained elusive. Our study reveals that germinal center IgA responses are essential for preventing chronic colonization of the gut by specific viruses. In the absence of IgA, chronic viral colonization triggers an antigen-driven expansion of CD8αβ⁺ intraepithelial lymphocytes (IELs). Although these IELs are unable to clear the virus, they contribute to maintaining homeostasis by regulating its load and type I interferon responses. Consequently, IgA deficiency increases susceptibility to colitis in genetically susceptible hosts or following chemical induction but only in the presence of viral pathobionts requiring IgA for their clearance. These findings underscore the potential vulnerability of IgA-deficient individuals to immunopathology when exposed to selective viral pathobionts.