CCR8 Expression on Regulatory T Cells Reveals Trajectories of Tissue Adaptation and Protects Against Myocardial Infarction–Induced Tissue Damage
Abstract
BACKGROUND: Tissue-specific regulatory T cells (Tregs) accumulate in the heart after myocardial infarction (MI) and play a vital role in limiting inflammation and promoting tissue repair. However, the developmental trajectory of heart Tregs and the molecular cues that guide their recruitment to the heart remain poorly understood, impeding therapeutic strategies that leverage Treg-mediated cardiac protection. METHODS: We used single-cell and bulk RNA sequencing in a murine MI model to delineate the differentiation trajectory of Tregs from mediastinal lymph nodes to the heart. Functional validation was performed using Treg-specific Ccr8 (CC motif chemokine receptor 8) knockout mice ( Ccr8 flox/flox Foxp3 Cre ), Ccl1 (CC motif chemokine ligand 1) knockout mice ( Ccl1 −/− ), macrophage-targeted Ccl1 knockdown mice, Ccl1 -overexpressing mice, and DEREG mice. The CCL1-CCR8 axis was evaluated in cardiac tissues and circulating blood from patients with MI. RESULTS: Single-cell RNA sequencing revealed a stepwise differentiation of mediastinal lymph node–derived naive Tregs into heart Tregs, marked by the progressive acquisition of CCR8 expression and reparative capacity. CCR8 + Tregs in the heart exhibited enhanced immunosuppressive and tissue-repair signatures. Treg-specific Ccr8 deletion led to reduced Treg accumulation and worsened cardiac function after MI, along with increased proinflammatory macrophage features and number of CD8 + T cells and natural killer cells. In addition, Tregs promoted a shift of macrophages toward an anti-inflammatory phenotype by secreting IL-1R2 (interleukin 1 receptor, type 2). We identified cardiac macrophages as the main source of CCL1, which was essential for CCR8 + Treg recruitment. Ccl1 deficiency or macrophage-specific Ccl1 knockdown impaired Treg infiltration and aggravated ventricular remodeling; Ccl1 overexpression promoted Treg recruitment and improved cardiac outcomes. Moreover, the cardioprotective effects of CCL1 were abolished in DEREG mice upon Treg depletion and Ccr8 flox/flox Foxp3 Cre mice, establishing a CCR8 + Treg-dependent mechanism. Furthermore, circulating CCR8 + Tregs and cardiac CCL1 were elevated in humans with MI, and the presence of CCR8 + Tregs and CCL1-expressing macrophages was confirmed in the hearts of patients with MI, suggesting important clinical relevance. CONCLUSIONS: Our findings reveal a 2-phase Treg specialization process and establish the CCL1-CCR8 axis as a crucial pathway for Treg recruitment and function in the infarcted heart. Therapeutic targeting of this axis may improve immune-regulated cardiac repair after MI.
Article Details
Authors (23)
Nana Li
Zhiheng Hao
Department of Cardiology (N.L., Z.H., H.Y., M.L., J.H., R.G., Y.S., Z.C., Y.L., T.T., M.Z., J.J., F.Y., J.L., M.G., N.X., X.C.), Huazhong University of Science and Technology, Wuhan, Hubei, China.
Haoyi Yang
Beijing Frontier Research Center on Clean Energy
Jie Cai
National and Local Joint Engineering Research Center of MPTES in High Energy and Safety LIBs, Engineering Research Center of MTEES (Ministry of Education), Research Center of BMET (Guangdong Province), and Key Lab. of ETESPG(GHEI), School of Chemistry
Meilin Liu
School of Materials Science and Engineering
Junyi He
Rui Gao
Yuhan Shen
State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences–Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology
Zhehao Chen
Department of Cardiology (N.L., Z.H., H.Y., M.L., J.H., R.G., Y.S., Z.C., Y.L., T.T., M.Z., J.J., F.Y., J.L., M.G., N.X., X.C.), Huazhong University of Science and Technology, Wuhan, Hubei, China.
Yuzhi Lu
Tingting Tang
Min Zhang
Jiao Jiao
School of Chemistry, Institute of New Concept Sensors and Molecular Materials (INCSMM), State Key Laboratory of Fluorine & Nitrogen Chemicals, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi’an Key Laboratory of Sustainable Polymer Materials
Fen Yang
Jingyong Li
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Muyang Gu
Department of Cardiology, Hubei Key Laboratory of Biological Targeted Therapy, Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (M.Z., Y.Y.Q., T.Z., M.L.L., T.T.T., N.X., S.F.N., B.J.L., Z.F.Z., J.J., M.Y.G., J.Y.L., X.C.).
Desheng Hu
Weimin Wang
MAX IV Laboratory, Fotongatan 2, Lund, SE-22484, Sweden
Qing Wang
Chen Chen
Zhilei Shan
Department of Nutrition and Food Hygiene (Z.L.S.), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ni Xia
Department of Cardiology, Hubei Key Laboratory of Biological Targeted Therapy, Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (M.Z., Y.Y.Q., T.Z., M.L.L., T.T.T., N.X., S.F.N., B.J.L., Z.F.Z., J.J., M.Y.G., J.Y.L., X.C.).
Xiang Cheng