PROJECT SUMMARY Cancer patients receiving Doxorubicin (Dox) chemotherapy often develop cardiac complications which can result in heart failure (HF). Some of the prominent hallmarks of Dox HF patients are cardiac fibrosis, cardiac atrophy, systolic dysfunction as well as heightened systemic inflammation. Cardiac fibrosis and cardiac inflammation often coincide in nearly all forms of HF, and while the concept that cardiac fibroblasts, a heterogeneous and plastic cell type in response to stressors, and immune cells communicating with each other to exert cardiac pro-fibrotic and pro-inflammatory responses is emerging, it remains incompletely understood, and the immune and fibrotic mechanisms involved in Dox HF are understudied. My lab previously reported that one way of communicating is that cardiac fibroblasts can function as antigen presenting cells through the major histocompatibility complex class II (MHC-II), which is induced by IFN-γ, and my preliminary data using a mouse model of Dox cardiomyopathy demonstrate increased expression of MHC-II on a subset of cardiac fibroblast, coinciding with increased infiltration of IFNγ+ T cell subsets and cardiac fibrosis. My data also demonstrate that MHC-II induction on cardiac fibroblasts is T cell dependent and that specific deletion of cardiac fibroblast MHC-II in mice results in preserved systolic function and decreased fibrosis. In two aims I will test the central hypothesis that Dox induces a pro-inflammatory cardiac fibroblast state characterized by MHC-II expression through T cell IFN-γ signals that contribute to cardiac fibrosis and pathophysiology. In SA1, I will investigate the mechanisms by which MHC-II on cardiac fibroblasts contribute to T cell immune responses and cardiac fibrosis during the progression of Dox cardiomyopathy. In SA2, I will interrogate whether cardiac fibroblast MHC-II expression dictates fibroblast function and crosstalk with T cells in Dox cardiomyopathy. I will combine in vitro and in vivo gain and loss of function approaches. Overall, my project will identify novel mechanisms in the fibroblast-T cell interface that may be targeted to ameliorate Dox cardiomyopathy, while supporting my PhD training.