Letter by Wang et al Regarding Article, "Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy".

June 11, 2019 e1033 Daxin Wang, MD Xinquan Yang, MD Honyan Zhong, MD To the Editor: We read with great interest the recent publication by Bansal et al1 highlighting the essential role of dysfunctional and proinflammatory regulatory T-lymphocytes (Tregs) in the mice model of chronic ischemic cardiomyopathy. The striking finding was that normalization of the immunocompromised Tregs phenotype that exhibited proinflammatory T helper 1-type features, and impaired immunoregulatory capacity, was crucial for reverse of cardiac remodeling during chronic heart failure (CHF). Correction of insulin resistance (IR), which is prevalent among patients with heart failure, proved to be one considerable therapeutic target for ameliorating cardiac remodeling in CHF.2 We wonder whether the dynamic change of IR might be involved in the pathological conversion of Tregs during progression of CHF or whether the restoration of normal Tregs function by the methods mentioned in the Bansal et al study would also regulate the states of IR in investigating the possible feedback of Tregs function and IR. High levels of insulin could impair the ability of Tregs to inhibit inflammatory response through the activation of the AKT/mTOR signaling pathway.3 Hence, we considered that it was necessary to evaluate whether hyperinsulinemia, hyperglycemia, and other potential factors in the setting of IR would be promising clues to help explain the metabolic reprogramming in reexpanding circulating Glut1hi Tregs. E3 ubiquitin ligase VHL could regulate hypoxia-inducible factor-1α (HIF-1α) to maintain Tregs stability and suppressive function. In addition, the downregulation of Foxp3 (forkhead box protein P3) expression was associated with excessive interferon-γ (IFN-γ) production of Tregs, and increased HIF-1α—which could bind directly to the Ifng promoter and then induce glycolytic reprogramming in Tregs—was required for its IFN-γ production.4 This study suggested that detecting the dynamic expression of the HIF-1α/IFN-γ/ Foxp3/VHL pathway in Tregs from the heart, lymph nodes, blood, spleen, and other sources should be carried out in an extended study to understand the conversion of IFN-γ+ Tregs during CHF, and to explore the effects of cardiac microenvironments on phenotype and characterization of Tregs. Data reported from a recent study about mice deficient in epicardial YAP and TAZ exhibited significantly higher mortality rates and fewer suppressive Tregs in the injured zones, highlighting the important role for epicardial signals in regulating the adaptive immune response after myocardial infarction.5 Thus, we strongly suggest that the available survival analysis be showed in this elegant study, or involved in extended studies to support the significant clinical implication of normalization of Tregs function during CHF, and future studies could focus on the role of signals from epicardial tissue, such as epicardial adipose tissue and others, in the regulation of Tregs phenotype and function in more experimen© 2019 American Heart Association, Inc. LETTER TO THE EDITOR