The earlier FIRST award focused on elucidation of the underlying molecular and cellular mechanisms for the induction and regulation of antigen-specific secretory IgA (S-IgA) antibody (Ab) responses at mucosal surfaces with emphasis on the salivary glands. The earlier studies have produced important results indicating that a mucosal intranet consisting of alpha,beta-T cells, gammadelta T cells and epithelial cells played major roles in the induction and regulation of antigen-specific IgA Ab responses. Thus, nasal immunization with the weakly immunogenic protein ovalbumin (OVA) and the nonenterotoxic mutant cholera toxin (CT) as mucosal adjuvant induced Th2-type cytokine-mediated salivary S-IgA Ab responses. Interestingly, depletion of gammadelat T cells resulted in impaired mucosal IgA responses including those responses in saliva. Further, these findings showed that epithelial cells produced an important cytokine, i.e., interleukin (IL)-7 which is central to the development and differentiation of alphabeta T cells. These results clearly indicate that lymphocyte- epithelial cell interactions, representing innate and acquired immunity, are part of the mechanisms involved in the induction of antigen-specific IgA Ab responses. These findings suggest that the innate immune system may be a key element in bridging innate with acquired mucosal immunity as manifested by antigen-specific IgA responses. Recent studies have indeed shown that nasal application of defensins, or chemokines such as lymphotactin or RANTES with OVA induced OVA-specific mucosal IgA Ab responses, including those associated with the salivary glands. Further, most recent findings through this grant effort showed that mRNA for these chemokines were expressed by intestinal and salivary gammadelta T cells as well as by epithelial cells. Thus, the overall hypothesis in this grant renewal application will be that the innate mucosal immune system plays an especially important role in acquired immunity for the induction and regulation of salivary gland IgA Ab responses. In order to understand the precise cellular and molecular mechanisms involved in innate immunity for mucosal IgA responses, the following Specific Aims are proposed. Specifically, there are plans to: 1) Characterize innate immunity in salivary glands of mice immunized with a hapten-LPS derivative of T-independent (TI) antigen ; 2)Examine the roles for innate immunity-associated mucosal modulators for the induction of TI-antigen-specific immunity in the salivary gland ; 3) The bridging mechanisms between immunity for the induction of antigen-specific immune responses in salivary glands induced by specific mucosal adjuvants and delivery systems ; 4) Assess the roles of gammadelta T cells in the salivary intranet which bridge innate with acquired immunity ; and 5) Determine how innate gammadelta T cells-CD4 about alphabeta T cells interact for IgA responses in the SMG.
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