Commensal bacteria colonize the gut mucosa, and secretion of IgA, the most abundant antibody type in mucosal secretions, by the gut is required to maintain immune homeostasis, promote tolerance and defend against pathogens in the presence of commensals.

A recent study now shows that the programmed cell death-1 (PD-1) inhibitory co-receptor regulates the microbiota by selecting the appropriate IgA repertoire (Science 336, 485–489). Using mice lacking PD-1, Kawamoto et al. found that its deficiency perturbed the bacterial composition. Although the number of IgA-producing cells in the lamina propria, the mucosal layer that recruits immune effector cells, stayed the same, there was a change in the IgA repertoire and less coating of bacteria by IgA in PD-1–deficient mice.

The altered IgA repertoire seen in PD-1–deficient mice seems to occur because of an increased turnover of IgA-producing cells in the lamina propria, an effect that was abrogated after antibiotic treatment, suggesting that the microbiota drives selection of IgAs at this site. The authors also observed a more rapid transit of B cells through germinal centers located in lymphoid structures, where antibody affinity maturation and diversification occur. Within germinal centers, T follicular helper (TFH) cells help out B cells and promote their differentiation into antibody-secreting cells or memory B cells. In the germinal centers of PD-1–deficient mice, TFH cells were more abundant and had a skewed cytokine profile, which may alter the selection of B cells and cause changes in the types of gut IgAs that they produce.

As mice lacking PD-1 showed hyperactivation of the immune system and production of antibodies against commensals, these findings suggest PD-1 absence may cause loss of tolerance. Further studies should investigate the role of PD-1 in autoimmune diseases in humans and its potential as a target to modulate these diseases.