IgA B cell receptor signaling protects from FasL counterselection during germinal center reaction in Peyer’s patches and shapes humoral mucosal response.

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Abstract Immunoglobulin A (IgA) is the main antibody isotype found in the intestine: deficiency in IgA alters microbiome composition, leads to increased susceptibility to enteric pathogens and reduces tissue response to oral vaccine. IgA can bind multiple unrelated bacterial taxa, but mechanistic insights into the generation of such cross-species reactivity are lacking. IgA+ B cells arise during germinal center (GC) reaction in Peyer’s patches: however, the role of IgA B cell receptor (BCR) in shaping the humoral response at the intestinal interface remains unknown. Here we showed that GC B cells lacking IgA are rapidly outcompeted by IgA+ B cells during GC reaction in Peyer’s patches and they are unable to contribute to memory B cell and intestinal-homing plasma cell compartments. IgA BCR did not impact cell proliferation in dark zone, and ectopic Bcl-2 expression was unable to rescue IgA-deficient GC B cells in mixed bone marrow chimeras. In contrast, IgA-deficient GC B cells underwent increased apoptosis in the light zone. In line with these findings, we observed that IgA BCR mediated faster and stronger intracellular Ca2+ signaling and led to increase BCR-dependent phosphorylation events. Mechanistically, IgA BCR signaling conferred resistance to Fas ligand (FasL)-dependent cell death in vitro, and genetic inhibition of Fas-FasL pathway restored IgA-deficient B cell fitness during GC reaction in vivo. Thus, our results showed that IgA-expressing GC B cells are protected from FasL counterselection in the light zone via enhanced BCR intracellular signaling. This process might allow low affinity B cell clones to participate to the GC reaction and assure a comprehensive humoral response to poorly immunogenic commensal species. Supported by grants from NIH (T32 AI132152, T32 AI007349 and R01 AI155727-02)