A Gut Feeling: The mammalian gut is colonized by many nonpathogenic, commensal microbes. In order to prevent the body from mounting inappropriate immune responses to these microbes, plasma cells in the gut produce large amounts of immunoglobulin A (IgA) specific for commensal bacteria. Because of the difficulties of uncoupling IgA production from microbial colonization, how commensal bacteria shape the gut IgA response is not well understood. Hapfelmeier et al. (p. 1705 ; see the Perspective by Cerutti ) have now devised a way to get around this problem by developing a reversible system of gut bacterial colonization in mice. Commensal-specific IgA responses were able to persist for long periods of time in the absence of microbial colonization and required the presence of high microbial loads in the gut for their induction. IgA responses upon bacterial reexposure did not resemble the synergistic prime-boost effect seen in classical immunological memory responses but rather exhibited an additive effect that matched the current bacterial content present in the gut. The body thus constantly adapts the commensal-specific immune response to the microbial species present in the gut, which contrasts with the systemic immune response, which persists in the absence of pathogenic microbes.

Toll‐like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub‐types, including PDC, but that TLR3 is preferentially expressed by CD8α⁺ DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8α^– DC and PDC, but not CD8α⁺ DC as measured by survival ex vivo, up‐regulation of surface markers and production of IL‐12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non‐plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8α⁺ DC in recognition of certain mouse pathogens.

Secretory IgA has long been a divisive molecule. Some immunologists point to the mild phenotype of IgA deficiency to justify ignoring it, while some consider its abundance and evolutionary history as grounds for its importance. Further, there is extensive and growing disagreement over the relative importance of affinity-matured, T cell-dependent IgA vs. “natural” and T cell-independent IgA in both microbiota and infection control. As with all good arguments, there is good data supporting different opinions. Here we revisit longstanding questions in IgA biology. We start the discussion from the question of intestinal IgA antigen specificity and critical definitions regarding IgA induction, specificity, and function. These definitions must then be tessellated with the cellular and molecular pathways shaping IgA responses, and the mechanisms by which IgA functions. On this basis we propose how IgA may contribute to the establishment and maintenance of beneficial interactions with the microbiota.