Abstract The vast majority of IgA production occurs in mucosal tissue following T cell–dependent and T cell–independent Ag responses. To study the nature of each of these responses, we analyzed the gene-expression and Ig-reactivity profiles of T cell–dependent CD27+IgA+ and T cell–independent CD27−IgA+ circulating memory B cells. Gene-expression profiles of IgA+ subsets were highly similar to each other and to IgG+ memory B cell subsets, with typical upregulation of activation markers and downregulation of inhibitory receptors. However, we identified the mucosa-associated CCR9 and RUNX2 genes to be specifically upregulated in CD27−IgA+ B cells. We also found that CD27−IgA+ B cells expressed Abs with distinct Ig repertoire and reactivity compared with those from CD27+IgA+ B cells. Indeed, Abs from CD27−IgA+ B cells were weakly mutated, often used Igλ chain, and were enriched in polyreactive clones recognizing various bacterial species. Hence, T cell–independent IgA responses are likely involved in the maintenance of gut homeostasis through the production of polyreactive mutated IgA Abs with cross-reactive anti-commensal reactivity.