It has been the standard dogma that preformed CD8+ memory T cells, generated through exposure to environmental antigens and infectious agents, present a barrier to acceptance of solid organ allografts. Our laboratory has made the surprising observation that, in stark contrast to other organs, CD8+ memory cells with the CD8+CD44hiCD62LhiCCR7+ central memory phenotype play a critical role in lung allograft tolerance induction. The overall goal of this application is to perform mechanistic studies in the mouse vascularized orthotopic lung transplantation model to investigate cellular mechanisms contributing to the tolerogenic function of this cell population. In the first aim we will focus on mechanism contributing to the local accumulation of CD8+ central memory T cells, including cellular mechanisms contributing to their homing and maintenance of differentiation. In the second aim we will investigate the role of CD8+ central memory cells in the local accumulation of inducible nitric oxide producing myeloid cells. In the third aim we will characterize how neutrophils affected by extended ischemia/reperfusion injury prevent CD8+ central memory T cell-mediated lung allograft acceptance.
Patients that receive an organ transplant are often treated with protocols to deplete or inactivate their T cells. We have recently demonstrated that unlike the case for other organs, depletion of some T cells maybe deleterious after lung transplantation. This grant application explores the immunologic basis for transplant acceptance of lungs. Results from this application could improve the long-term survival of lung transplant recipients.
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