Gamma-delta T cells: their atherogenic actions and therapeutic potential in atherosclerosis

Abstract Introduction Atherosclerosis, a chronic inflammatory disease of the arteries, is a major contributor to ischemic attacks in the heart. Immune cells are studied in atherosclerosis and recognized as important players in plaque instability; however, multipotent γδ-T cells are rarely studied. Here, we aim to investigate their role in chronic arterial inflammation and the therapeutic potential of targeting them in preventing plaque instability. Methods Depletion and repletion strategies were adopted to examine the critical role of bone marrow derived γδ-T cells in atherosclerosis. Their direct atherogenicity mediated by interferon- γ (IFN-γ) and perforin (pfp) was investigated in mixed chimeric mice with specific protein deficiency restricted to bone marrow derived γδ-T cells. Anti -mouse TCR γ/δ antibody was employed to examine the master regulatory role of γδ-T cells in plaque stability. Mice with established atherosclerosis were treated with small molecule CXCR3-antagonist, AMG487 to retard γδ-T cell-modulated plaque instability. Results We confirmed that bone marrow derived γδ-T cells promote atherosclerosis and plaque stability. They directly contribute to lesion inflammation and cell death via IFN-γ and pfp leading to expanding vulnerable plaques. In addition, γδ-T cells express innate activating receptors, NKG2D and DNAM-1, for their activation in lesion and activated γδ-T cells recruited proinflammatory and cytotoxic immune cells via chemoattractants Rantes and MIP-1α, suggesting their pivotal roles in lesion progression. AMG487 treatment inhibited γδ-T cells and other immune cells and reduced atherosclerotic lesions with stable plaque characteristics - less cytotoxicity, more vascular smooth cells and thicker caps. Conclusion We have shown that bone marrow-derived CD27-positive γδ-T cells are most important immune cells in atherosclerosis. They contribute lesion cytotoxicity and inflammation by direct effector functions and influencing other atherogenic cells, and targeting them with AMG487 may be beneficial to reduce generation of vulnerable plaques and subsequent rupture so that it can significantly reduce MI.