A large fraction of the intestinal commensal microbiota is coated with IgA antibodies in homeostatic conditions, but the strategy and the mechanisms deployed to confront the 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 rate 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, and how they coexist or overlap with other immune responses during homeostasis and disease. This project addresses these issues by (i) generating polyreactive IgA knock-in mice using CRISPR/Cas9 technology to (ii) understand the development and differentiation of polyreactive IgA precursor B cells and (iii) to study the function of polyreactive IgA at the clonal level in the context of intestinal and extraintestinal challenges. These studies will clarify a major gap in our understanding of polyreactive B cell repertoires, address a challenge to existing dogmas of antibody specificity and tolerance, and develop new knowledge, concepts and tools for a better understanding of intestinal immunity, inflammatory bowel diseases and oral vaccines.

R01AI144094

2019-01-17

2023-12-31