Determining the location and phenotype requirement of CD4 T cells in schistosomiasis pulmonary hypertension

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PROJECT SUMMARY / ABSTRACT This Supplement will support Ms. Dara Fonseca Balladares for 1 year following completion of her baccalaureate to help her achieve her career goals of attending medical school in an MD-PhD program, and becoming an independent physician scientist. This research fellowship will provide Ms. Fonseca Balladares with technical skills to perform experiments; cognitive skills to plan experiments, interpret results and plan appropriate next steps; and additional education in research including ethics and immunology (relevant to this research project now, and her future career in medicine). Ms. Fonseca Balladares will complete a detailed plan of progressive milestones outlined in the proposal, including acquiring experimental techniques and formulation of novel hypotheses. She will participate in several career development programs at the University of California Berkeley and San Francisco, including formal coursework in topics relevant to the research project and her career goals. She will work with the PI Graham and a pre-identified career development advisory committee, who will monitor the course of her experimental research plan and career development training. It is expected that Ms. Fonseca Balladares will present her work at the ATS international conference, and publish a first author paper reporting her findings obtained in completing the proposed research. Ms. Dara Fonseca Balladares’ research project will investigate the phenotype and location requirement of CD4 T cells in schistosomiasis-induced pulmonary hypertension (PH). The mouse model we use employs intraperitoneal (IP) sensitization prior to intravenous (IV) challenge with Schistosoma eggs to cause PH, and we have shown Th2 CD4 T cells are necessary and sufficient for Schistosoma-induced PH, which direct Type 2 inflammation that causes recruitment of Ly6c+ monocytes which express thrombospondin-1 (TSP-1), resulting in TGF-β activation which induces pathologic phenotypes in the vascular cells. An initial preliminary experiment suggested that there are activated CD4 T cells in the lungs which do not require migration from lymph nodes to trigger inflammation-induced PH, as FTY720 which arrests T cells in lymph nodes did not block the PH phenotype. The supplement hypothesis is thus that primed and pre-positioned T cells in the lung are sufficient to induce Type 2 immune-driven Schistosoma PH with IV egg challenge. Specific Aim 1 of the supplement will describe the numbers and phenotype of CD4 T cells in lymph nodes and lung tissue following IP sensitization and IV egg challenge. Specific aim 2 of the supplement will determine if CD4 T cells already present in the lungs are sufficient to induce Type 2 immunity and Schistosoma-induced PH. Overall this topic is within the scope of the parent grant, which seeks to determine the functions of dendritic cells and CD4 T cells which are necessary for Schistosoma-PH, by now seeking to identify the specific location requirement of CD4 T cells.