Tissue resident memory T cells and chronic lung allograft dysfunction

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Project Summary Lung transplantation remains the only definitive treatment for many patients with end stage lung disease. However, the outcomes after lung transplant are meager when compared to other solid organ transplants, with a median survival of only 6 years. The major limiting factor to long-term survival after lung transplantation is the high incidence of chronic lung allograft dysfunction (CLAD), a progressive form of a lung allograft failure associated with high morbidity and mortality affecting half of all transplant recipients by 5 years. Episodes of acute cellular rejection, a T cell mediated allo-immune inflammation of the lung allograft, are associated with increased risk of CLAD. Our group previously showed that T cells recruited to the lung during acute cellular rejection persist within the allograft as tissue resident memory T cells (TRM) and that these TRM migrate to the airways, the site of tissue pathology in CLAD. The focus of this application is to identify whether lung allograft TRM are alloreactive and how TRM may interact with their local environment to contribute to the development of CLAD. Importantly, our preliminary data suggests that systemic immune modulators do not impact lung TRM in the same way that they effect circulating immune cells. This application plans to advance our understanding of how commonly used immunosuppressants, like alemtuzumab, basiliximab, glucocorticoids, and cyclosporine impact the phenotype, function, and persistence of lung TRM compared to circulating T cells. Our research aims include: 1) Identify the alloreactive potential of recipient-derived allograft TRM in lung transplant recipients with and without CLAD; 2) Establish the role of lung resident myeloid cells in the maintenance of alloreactive recipient- derived lung TRM; and 3) Determine the impact of systemic and inhaled immune modulators on lung TRM persistence and function. The results of these investigations explore a mechanism where alloreactive T cells contribute to CLAD and elucidate how existing immune modulators impact TRM phenotype and function.