Local and peripheral mechanisms of T cell-mediated immune regulation after lung transplantation

PROJECT SUMMARY / ABSTRACT Long-term outcomes after lung transplantation continue to be limited by the development of chronic lung allograft dysfunction, which may result from breakdown of immunoregulatory circuits. We have shown that deleterious alloimmune responses are downregulated through immune cell encounters in tertiary lymphoid organs that are induced in tolerant lung allografts. Our research has shown that Foxp3+ cells that accumulate in these structures play a central role in maintaining a tolerant state, both locally and peripherally. We have demonstrated that tertiary lymphoid organs in tolerant lung allografts are dynamic and that continuous recruitment of Foxp3+ cells is required to maintain tolerance. Furthermore, Foxp3+ cells that enter tolerant lung allografts acquire unique phenotypic and transcriptional characteristics, including increased expression of amphiregulin and CTLA4. In this project we will examine the role of amphiregulin in maintaining lung allograft tolerance vs. mediating chronic lung allograft dysfunction (Aim 1). We will assess mechanisms how Foxp3+ cells maintain local and peripheral tolerance (Aim 2). We will also evaluate the role of antigen presentation by stromal cells that are prevalent in tertiary lymphoid organs of tolerant lung allografts (lymphatic endothelial cells, fibroblastic reticular cells) in maintaining tolerance (Aim 3). In conjunction with Projects 2 and 3, these proposed studies will lay the foundation for new therapeutic strategies to improve outcomes after lung transplantation.