DESCRIPTION (provided by applicant): Effective vaccines would mitigate the impact of schistosomiasis in endemic regions that continue to experience high morbidity and transmission despite implementation of chemotherapy. However, a major problem with vaccine development is the lack of understanding of human immunity to schistosomiasis. A consistent correlate of resistance is elevated parasite-specific IgE, but the functional significance of IgE in mediating protection is undefined. We have found that IgE and CD23 work in concert to increase B cell responsiveness to schistosomes. Our published work suggests that CD23-bound IgE promotes mobilization of B cells from the circulation to the follicular regions of the spleen where CD23 also mediates antigen presentation to a broad repertoire of T cell clones. Our new data indicates that CD23-activated B cells promote specific subsets of CCR3+ T cells that may be important in generating protective Th2-immune responses. Thus, our central hypothesis is that schistosome-specific IgE mediates circulating CD23+ B cell trafficking and T cell activation pathways critical for developing resistance. Our key innovation is defining alternate, previously unexamined for roles for IgE and CD23 in human helminthiasis and immunity. In Specific Aim 1, we define the role of CD23-bound IgE in B cell trafficking through a collaboration with the Kenyan Medical Research Institute We will prospectively characterize the expression of CXCR5 on specific clones of CD23+ B cells during the development of age-acquired resistance in a pediatric cohort. We will determine the role of CD23-bound IgE in antigen and cellular trafficking in vitro through modeling experiments to define the B cell phenotypes and function associated with resistance in the field. In Specific Aim 2, we will define the role of B cell CD23-bound IgE o Th2 cell activation critical for augmenting protective Th2 responses through induction of CCR3+ T cells. We will prospectively and mechanistically determine the suppressive effects of CD23-bound polyclonal IgE on the ability to generate resistance and Th2 immunity towards explaining chronic susceptibility. Evidence that schistosomes cleave CD23 and release a unique soluble (s) CD23 fragment with immuno-suppressive functions will inform Specific Aim 3 studies where we will detail how this fragment suppresses IgE production and granulocyte-mediated killing of schistosomes. Altogether, our proposal will define novel and beneficial functions of IgE and potential strategies to vaccinate against schistosomiasis. Our results will fill current large gapsin our knowledge of human immunology with important clinical significance.