Immunologically Active Cardiac Fibroblasts Expressing Major Histocompatibility Complex-II Promote Doxorubicin...

A common adverse effect of the chemotherapeutic anthracycline, doxorubicin, is cardiotoxicity and progression to heart failure. Patients treated with anthracyclines show increased circulating cytotoxic CD8⁺ interferon (IFN)-γ⁺ T cells. In mice, cumulative doses of doxorubicin also result in increased circulating and cardiac infiltrating CD8⁺IFN-γ⁺ T cells, and these cells are required for pathologic fibrosis and contractile dysfunction. The present study demonstrates that cardiac fibroblasts become immunologically active and express major histocompatibility complex (MHC) class II on the onset of doxorubicin cardiotoxicity in humans and in mice. Using adoptive transfer and in vitro mechanistic studies, the results show that CD8⁺IFN-γ⁺ T cells are required for cardiac fibroblast expression of MHC-II in mice treated with doxorubicin, and that doxorubicin induces cardiac fibroblast expression of CXCL9, resulting in CD8⁺IFN-γ⁺ T-cell cardiotropism. Selective deletion of MHC-II in cardiac fibroblasts ameliorates systolic dysfunction and dampens cardiac fibrosis induced by doxorubicin in mice. Mechanistically, this study shows that cardiac fibroblast MHC-II is required for cardiac CD4⁺IFN-γ⁺ T-cell infiltration and proliferation, necessary for cardiac CD8⁺ T-cell immune responses and cytotoxicity. These results position cardiac fibroblast MHC-II as a key mediator of contractile dysfunction in doxorubicin cardiotoxicity.