Background: Invariant natural killer T (iNKT) cells are a unique subset of the innate immune system activated by T cell receptor (TCR) signaling through CD1d molecules presenting lipid antigens. Tissue-specific iNKT cells are critical in maintaining homeostasis and regulating pathophysiology. However, the potential roles of iNKT subsets in mitigating cardiac damage remain poorly understood. In this study, we examined the role of cardiac iNKT subsets and their response to TCR-directed αGalCer/CD1d complexes in a mouse model of Doxorubicin (Dox)-induced cardiotoxicity. Methods: A chronic model of Dox-induced cardiotoxicity was developed in C57BL/6J mice. After the fourth dose of Dox treatment, mice were randomly divided into two groups and intraperitoneally administered either CD1d-empty monomer (Dox+empty/CD1d) or αGalCer/CD1d (Dox+αGalCer/CD1d) (20 μg/mouse/week, dissolved in phosphate-buffered saline) for 7 weeks. The control mice were administered with PBS. iNKT cell expansion in the heart was analyzed by flow cytometry. Cardiac function was assessed by echocardiography, and histological analyses were used to evaluate cardiac remodeling. Results: Our findings reveal that the heart predominantly harbors the pro-inflammatory iNKT1 subset, with smaller populations of anti-inflammatory iNKT2 and iNKTR1 subsets. Under homeostatic conditions, treatment with αGalCer/CD1d complexes preferentially expanded the iNKT1 subset. In Dox-induced cardiotoxicity, αGalCer/CD1d treatment favored iNKT1-derived Ifng expression. These observations suggest that αGalCer/CD1d treatment skewed the cardiac iNKT cell population towards the iNKT1 subset, potentially altering the inflammatory balance within the heart. However, it did not exacerbate cardiac damage, likely due to compensatory IL-10 production by an unidentified regulatory subset. Overall, αGalCer/CD1d treatment promoted the expansion of iNKT1 cells and elevated IFN-γ levels with modest therapeutic effects on cardiac function. Conclusion: These findings highlight the importance of iNKT-mediated cardiac immune regulation in the heart and emphasize the potential of targeting iNKT cells for therapeutic benefit. Further studies are warranted to determine if TCR-directed immunotherapeutics could be modified to skew immune responses for effectively treating inflammatory cardiac diseases.
Singh et al. (Fri,) studied this question.