IgA Responses to Microbiota

Abstract

Various immune mechanisms are deployed in the mucosa to confront the immense diversity of resident bacteria. A substantial fraction of the commensal microbiota is coated with immunoglobulin A (IgA) antibodies, and recent findings have established the identities of these bacteria under homeostatic and disease conditions. Here we review the current understanding of IgA biology, and present a framework wherein two distinct types of humoral immunity coexist in the gastrointestinal mucosa. Homeostatic IgA responses employ a polyreactive repertoire to bind a broad but taxonomically distinct subset of microbiota. In contrast, mucosal pathogens and vaccines elicit high-affinity, T cell-dependent antibody responses. This model raises fundamental questions including how polyreactive IgA specificities are generated, how these antibodies exert effector functions, and how they exist together with other immune responses during homeostasis and disease.

Figure 1. IgA-coated bacterial taxa and mechanisms of targeting

A) The IgA repertoire is enriched in natural polyreactive IgA antibodies that can bind multiple self and bacterial antigens with low affinity. Individual antibodies can react against lipopolysaccharides (LPS), capsular polysaccharides, flagellin, DNA, and other antigens, and may target multiple surface antigens in vivo. B) Summary of bacterial taxa that are targeted by IgA in vivo and the humoral mechanisms that lead to their coating, as determined by IgA-seq. The requirements for IgA targeting are based on Ig-seq studies of Tcrb^−/−d^−/−, CD4-cre Bcl-6f^l/fl, or Aicda^−/− mice lacking T cells, Tfh, or SHM and CSR, respectively. Properties of coating antibodies are based on polyreactivity ELISAs and Ig-seq using individual mAbs.

Figure 2. Mechanisms of IgA selection in Peyer’s patches

Natural polyreactive antibodies arise at low frequencies in the naïve B cell repertoire and recirculate through secondary lymphoid organs including GALT such as PPs. Upon reaching PPs, polyreactive cells are preferentially induced to divide in a manner that may involve reactivity with self-antigens. Upregulation of CCR6 drives migration to the subepithelial dome (SED), where cells receive TGFβ1 signals that induce IgA CSR via a mechanism that requires SED DC activation of latent TGFβ1 through the integrin αvβ8. After initiating CSR, B cells migrate back to the follicle where they can differentiate through either TD or TI pathways. During homeostasis, polyreactive and microbiota-reactive specificities differentiate via either a TI pathway lacking SHM or affinity maturation, or a TD pathway that accumulates SHM but shows little affinity maturation and may include both GC and extrafollicular contributions. This contrasts with TD responses to pathogens that are typically non-polyreactive and show extensive SHM and affinity maturation in GCs. TNF-superfamily receptor-ligand interactions contribute to both TD (CD40-CD40L) and TI (BAFF/APRIL-TACI) pathways. Cells are imprinted for gut homing by induced upregulation of integrin α4β7 and the chemokine receptors CCR9 and CCR10. Lymphoblasts leave the PPs via lymphatics and transit through the thoracic duct to reenter blood circulation, which facilitates their migration to mucosal effector sites such as the intestinal LP, BM, or LMG.

Figure 3. Maternal antibodies impact neonatal microbiota and immunity

During postpartum lactation, IgA, IgG2b, and IgG3 antibodies are transferred to neonates via breast milk. These antibodies coat the neonatal microbiota and restrain the differentiation of CD44⁺ effector T cells, GCs, and IgA⁺ PCs in the mucosa, perhaps by preventing bacterial translocation.

Figure 4. Potential functions of IgA antibodies

Numerous potential functions for IgA antibodies have been suggested that may or may not play a role in vivo in the context of homeostatic interactions with the commensal microbiota. These include immune exclusion, neutralization, altered motility, modulation of gene expression, niche occupancy, and enhanced antigen uptake.