Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8⁺ T cells via CXCL16-CXCR6 axis after myocardial infarction

<b>Background:</b> Infiltrated CD8⁺ T cells following myocardial infarction (MI) are potential myocardial injury factors, triggering autoimmunity by binding to myocardial cell-specific proteins. It has been reported that autoimmunity after MI is restricted during the fibrosis period. Nevertheless, the relevant mechanisms of this process have scarcely been explored. Cell-cell communication analysis suggests that macrophages are the most promising group for restricting T cell activity. Unbiased single-cell sequencing data screening indicates that TREM2 is a leading gene significantly upregulated after MI. However, how TREM2 restricts the activity of CD8⁺ T cells remains unknown. <b>Methods and Results:</b> The adoptive transfer of circulating CD8⁺ T cells after MI proved their autoimmune attribute of attacking cardiomyocytes. CD8 antagonistic antibodies and the anti-autoimmune drug Ozanimod effectively inhibited the infiltration of CD8⁺ T cells and significantly ameliorated the damage to cardiomyocytes after MI. In TREM2 KO mice, the infiltration of CD8⁺ T cells in the myocardium was significantly increased without influencing the number of Treg cells. The results of cell-cell communication revealed that CXCL16-CXCR6 was the most predominant receptor-ligand pair between macrophages and CD8⁺ T cells. The results of ELISA and Transwell indicated that TREM2 deficiency led to an increase in CXCL16 secretion, thereby enhancing the chemotaxis of CD8⁺ T cells. The KEGG analysis and Western Blot results demonstrated that the deficiency of TREM2 augmented the activation of the PI3K-AKT signaling pathway, thereby resulting in an increase in CXCL16 secretion. Moreover, TREM2 deficiency also reduced VEGFC secretion and cardiac lymphangiogenesis, thereby leading to the impairment of immune cell drainage. Additionally, TREM2 deficiency reversed Ozanimod's effect on inhibiting CD8⁺ T cell infiltration. The overexpression of TREM2 significantly decreased CD8⁺ T cell infiltration and improved cardiac function. <b>Conclusions:</b> Macrophage TREM2 promotes cardiac repair by limiting the infiltration of CD8⁺ T cells and facilitating lymphangiogenesis.