ADENOVIRUS FLT3 LIGAND INDUCES NALT DCs FOR SALIVARY GLAND S-lgA Ab RESPONSES

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DESCRIPTION (provided by applicant): Over the past five years, we have studied the innate factors and immune cells which induce and regulate salivary secretory immunoglobulin (S-lgA) antibody (Ab) responses. We have shown that plasmids encoding the flt3 ligand (FL), lymphotactin (LTN), RANTES and MCP-1 cDNA as well as unmethylated cytosine-guanine dinucleotides oligodeoxynucleotide (CpG ODN), when used as nasal adjuvants, enhance both mucosal and systemic immune responses. Nasopharyngeal-associated lymphoreticular tissues (NALT) and the submandibular glands (SMGs) from mice given these nasal cDNA adjuvants showed increased numbers of dendritic cells (DCs) and were a key factor in the induction of salivary S-lgA Ab responses. Further, our recent study using an adenovirus (Ad) expressing FL cDNA (pFL) when used as nasal adjuvant significantly enhanced salivary S-lgA Ab responses. Based upon these findings, our overall hypothesis in this renewal application is that NALT DCs regulate salivary S-lgA Ab responses by processing Ag followed by their migration into the SMGs. More specifically, we hypothesize that targeting NALT with FL-based adjuvants will preferentially induce migration of NALT DCs into the SMGs and enhance the induction of mucosal S-lgA Ab responses. Our recent study showed that T cell-independent (Tl) Ag-specific salivary S- IgA Ab responses correlated with an increased number of B-1 B cells in the SMGs when mice were immunized nasally with Tl Ag plus native cholera toxin. Further, we found that increased levels of Toll-like receptor four (TLR4) expression by 78 T cells in the SMGs of mice given nasal Tl Ag. These results clearly showed that cross-talk between innate- and acquired-type immune cells was important in the induction of Ag-specific salivary S-lgA Ab responses even for immune responses to Tl Ags. We hypothesize that targeting NALT with FL-based adjuvants induce migration of NALT DCs to the SMGs that interact with B-1 B cells and y& T cells in the SMGs for the induction of mucosal S-lgA Ab responses. In order to test our hypothesis, we propose four Specific Aims. We will: 1) Characterization of chemokine receptor expression by Ad-FL-induced CD11b+ DCs in NALT for their maturation and their relocation into the SMGs. 2) Tracking Ad-FL-induced NALT DC migration for the induction of salivary S-lgA Ab responses. 3) Comparison of Ad- FL-induced NALT and SMG DCs for their immunological function in the induction of CD4'1' Th1- and Th2-type cytokine responses as well as long-lasting memory function. 4) Determination of the precise mechanism for cross-talk between Ad-FL-induced salivary DCs, B-1 B cells and yS T cells for salivary S-lgA Ab responses.