Circulating human CD27^-IgA⁺ memory B cells recognize bacteria with polyreactive Igs

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 Igl 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 anticommensal reactivity.