Immune Checkpoints Are New Therapeutic Targets in Regulating Cardio-, and Cerebro-Vascular Diseases and CD4+Foxp3+ Regulatory T Cell Immunosuppression

Abstract

Review Immune Checkpoints Are New Therapeutic Targets in Regulating Cardio-, and Cerebro-Vascular Diseases and CD4+Foxp3+ Regulatory T Cell Immunosuppression Ying Shao 1,2,†, William Y. Yang 1,†, Gayani Nanayakkara 3,†, Fatma Saaoud 1,†, Mohammed Ben Issa 1,†, Keman Xu 1, Yifan Lu 1, Xiaohua Jiang 1,2, Sadia Mohsin 4, Hong Wang 2, and Xiaofeng Yang 1,2,* 1 Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA19140, USA 2 Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA19140, USA 3 Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT84112, USA 4 Aging + Cardiovascular Discovery Center (ACDC), Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA19140, USA * Correspondence: xfyang@temple.edu † These authors contributed equally to this work. Received: 6 September 2024; Revised: 29 September 2024; Accepted: 30 September 2024; Published: 26 November 2024 Abstract: Although previous reviews explored the roles of selected immune checkpoints (ICPs) in cardiovascular diseases (CVD) and cerebrovascular diseases from various perspectives, many related aspects have yet to be thoroughly reviewed and analyzed. Our comprehensive review addresses this gap by discussing the cellular functions of ICPs, focusing on the tissue-specific and microenvironment-localized transcriptomic and posttranslational regulation of ICP expressions, as well as their functional interactions with metabolic reprogramming. We also analyze how 14 pairs of ICPs, including CTLA-4/CD86-CD80, PD1-PDL-1, and TIGIT-CD155, regulate CVD pathogenesis. Additionally, the review covers the roles of ICPs in modulating CD4+Foxp3+ regulatory T cells (Tregs), T cells, and innate immune cells in various CVDs and cerebrovascular diseases. Furthermore, we outline seven immunological principles to guide the development of new ICP-based therapies for CVDs. This timely and thorough analysis of recent advancements and challenges provide new insights into the role of ICPs in CVDs, cerebrovascular diseases and Tregs, and will support the development of novel therapeutics strategies for these diseases.