Graft-Resident CD11c Cells are Critical for the Maintenance of Tolerance Following Lung Transplantation

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PROJECT SUMMARY/ABSTRACT: Long-term survival after lung transplantation remains profoundly limited by graft rejection. Immunosuppression for lung recipients is based on experiences with solid organ transplants, but may be having deleterious effects to the survival of pulmonary grafts as the fate of the transplanted lungs is determined by local immune cell interactions within the graft itself. Bronchus-associated lymphoid tissue (BALT) forms in tolerant lung allografts and is important for the maintenance of tolerance. BALT is rich in Foxp3+ regulatory T cells that aggregate around CD11c+ cells. Depleting graft-resident Foxp3+ T cells or CD11c+ cells results in antibody mediated rejection. Exactly how cells interact within the BALT to regulate tolerance remains unknown. Our laboratory surprisingly found that the abundance of Foxp3+ T cells were not impacted by depletion of CD11c+ cells. CCL17 and CCL22 are chemokines expressed by CD11c+ cells that can engage CCR4, a receptor predominantly expressed on regulatory T cells. Preliminary data from our laboratory show that CCL17 and CCL22 are expressed at significantly higher levels by CD11c+ cells in tolerant lung grafts when compared to CD11c+ cells in rejecting lungs. We aim to determine whether CD11c+ cells maintain tolerance after lung transplantation by mediating the spatial organization of Foxp3+ cells within the graft. A previously established model of mouse lung re- transplantation will be used to test our hypotheses. Results will be analyzed using a combination of methods, including flow cytometry, immunohistochemistry and blinded histology analysis. A novel imaging technology, known as intravital two-photon microscopy, will be used in multiple experiments to study the movement and spatial relationships of Foxp3+ cells and CD11c+ cells in real time. The results of our proposal will provide a framework to develop novel therapies to improve outcomes for lung transplant patients.