Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing

Wengang Hu; Xiaorong Zhang; Zhongyang Liu; Jiacai Yang; Hao Sheng; Zhihui Liu; Cheng Chen; Ruoyu Shang; Yunxia Chen; Yifei Lu; Xiaohong Hu; Yong Huang; Wenjing Yin; Xin Cai; Dejiang Fan; Lingfeng Yan; Jianlei Hao; Gaoxing Luo; Weifeng He

doi:10.1016/j.isci.2024.109545

Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing

iScience. 2024 Mar 21;27(4):109545. doi: 10.1016/j.isci.2024.109545. eCollection 2024 Apr 19.

Authors

Wengang Hu^{1

2}, Xiaorong Zhang^{1

2}, Zhongyang Liu³, Jiacai Yang^{1

2}, Hao Sheng⁴, Zhihui Liu^{1

2}, Cheng Chen^{1

2}, Ruoyu Shang^{1

2}, Yunxia Chen^{1

2}, Yifei Lu^{1

2}, Xiaohong Hu^{1

2}, Yong Huang^{1

2}, Wenjing Yin⁵, Xin Cai^{1

2}, Dejiang Fan^{1

2}, Lingfeng Yan^{1

2}, Jianlei Hao^{6

7}, Gaoxing Luo^{1

2}, Weifeng He^{1

2}

Affiliations

¹ State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
² Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China.
³ Department of Plastic Surgery, the First Affiliated Hospital, Zhengzhou University, Henan, China.
⁴ Urology Department, the Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China.
⁵ Academy of Biological Engineering, Chongqing University, Chongqing, China.
⁶ Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000 Guangdong, China.
⁷ The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, Guangdong, China.

Abstract

Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4⁺ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4⁺ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4⁺ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4⁺γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C⁺monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4⁺ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.

Keywords: Biological sciences; Components of the immune system; Immune response.