Th17 cell regulation of intestinal IgA production

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DESCRIPTION (provided by applicant): Immunoglobulin A (IgA) has been shown to be critical in mucosal immune defense. Intestinal IgA can be produced by both T cell-dependent and T cell-independent pathways, however, the relative importance of each and how they are regulated are still largely unclear. IL-17-producing CD4+ T (Th17) cells have recently been defined as a separate effector T cell lineage, important in host defense against certain infectious agents, as well as in the pathogenesis of some autoimmune diseases. Although high amounts of IgA and Th17 cells are both present constitutively in intestine, there is sparse data that addresses how each of these systems respond to antigens of the microbiota, or whether these two systems interact in that effort. Our preliminary data found impaired intestinal IgA production in IL-17R deficient mice. Conversely, adoptive transfer of Th17 cells induced intestinal IgA production in TCR¿xd-/- mice, indicating that Th17 cells play an important role in intestinal IgA production. The mechanism(s) of Th17 cell regulation of intestinal IgA responses is unknown, and the subject of this application. We recently identified enteric bacterial flagellins, which present in intestinal lumen, as immunodominant antigens in experimental colitis and in patients with Crohn's disease. We have generated a TCR transgenic mouse line that is specific for CBir1 flagellin, one of these commensal bacterial flagellins. We have crossed CBir1 Tg mice with IL-17F-Thy1.1 reporter mice and IFN?- Thy1.1 reporter mice. With these novel mice and reagents in hand, we will investigate how Th17 cells regulate intestinal IgA responses, and whether the putative Th17-IgA pathway is directed toward pathogens and toxins using cholera toxin (CT) as a surrogate pathogen. We hypothesize that 1) Th17 cells promote intestinal IgA production via mechanisms involving IL-17, IL-21, as well as CD40L-CD40 interactions; 2) Th17-IgA pathway mediates mucosal IgA response to cholera toxin, which depends on cholera toxin induction of IL-6 production.