Cellular and molecular mechanisms regulating immunoglobulin A production

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The gastrointestinal (GI) tract is the largest mucosal surface of the mammalian body and is heavily colonized by normally harmless microbes. A key mechanism required for establishing and maintaining a homeostatic balance between the intestinal microbiota and the lymphocytes that densely populate the GI tract is the production and trans-epithelial transport of poly-reactive Immunoglobulin (Ig) A. Within the mucosal tissues, B cells respond to cytokines, often in the absence of T cell help, undergo class switch recombination (CSR) of their Ig receptor to IgA, and differentiate to become plasma cells (PC). Our recent observations demonstrate that intestinal IgA+-secreting PC have acquired the ability to produce the anti-microbial mediators TNFa and iNOS and express many molecules that are commonly associated with monocyte/granulocytic cell types. These additional attributes are essential for coping with the tremendous bacterial load in the GI tract, since the deletion of TNFa and iNOS in B-lineage cells resulted in altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B lineage cells. To further decipher the molecular pathways regulated by iNOS and TNFa this research program will specifically explore the role of iNOS and TNF? for IgA+ PC cell development in the following contexts. (i) We hypothesize that iNOS and TNF? play a central role in regulating the function of the proprotein convertase furin as well as BAFF and APRIL, thereby instructing subsequent IgA CSR. (ii) We hypothesize that iNOS and TNF? play a central role in regulating the function of the TACI on mucosal B cells, thereby instructing subsequent IgA CSR. The outlined research program delineates two critical questions regarding the molecular and cellular mechanisms required for IgA CSR and the gained knowledge will be of utmost importance for our understanding of how we establish and maintain a homeostatic balance with our commensal microbiota.