Sequential class switching generates antigen-specific gut IgA from IgG1 B cells

Immunoglobulin (Ig)A is the primary isotype protecting the gut barrier, yet fundamental aspects of antigen-specific IgA induction remain unknown. Gut lymphoid organs are chronically exposed to foreign antigens, are structurally different from other lymphoid tissues, and are functionally unique. This suggests gut IgA induction occurs through noncanonical means. Indeed, we observed the generation of affinity-matured IgA B cells through both germinal center (GC) and nonGC pathways. Although most antibody isotypes are generated directly from naive IgM B cells, we discovered that IgG1 GC B cells can generate gut mucosal IgA in mice, with a similar relationship in mucosal and non-mucosal sites in humans. This supports a model of IgA generation through sequential class switching, linking the specificity of mucosal IgA and systemic IgG1 humoral immunity to gut-derived antigens. Defining these pathways is essential for the design of mucosal vaccines, which need to generate IgA and IgG antibodies for efficient barrier and systemic protection.