Specificity of Homeostatic IgA

A large fraction of the intestinal commensal microbiota is coated with IgA antibodies during homeostatic conditions, but the strategy and the mechanisms deployed to confront this immense diversity of bacterial antigens have remained elusive. Converging studies indicate that homeostatic IgA responses employ a highly polyreactive repertoire to bind broad but distinct subsets of microbiota. These antibody responses develop in the presence of limited T cell help, with low rates of somatic mutations and little affinity maturation. This new perspective contrasts with the classical paradigm of T cell-dependent, high-affinity antibody responses elicited by mucosal pathobionts, pathogens, and vaccines, and provides a simple immunological solution to the challenge of microbiota antigenic complexity. It also raises several fundamental issues, including how polyreactive specificities are generated and selected in the IgA repertoire, how these antibodies exert their effector functions, and how they coexist or overlap with other immune responses during homeostasis and disease.