Interleukin-23 receptor expressing gamma delta T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice

Aims Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and gamma delta T cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and gamma delta T cells in atherosclerosis. Methods and results IL-23R(+) cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr(-/-)Il23r(gfp/+)), and mostly identified as gamma delta T cells that express IL-17 and GM-CSF. scRNA-seq confirmed gamma delta T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr(-)(/)(-)Il23r(gfp/gfp) mice deficient in IL-23R showed a loss of IL-23R(+) cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr(-/-) controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr(-/-)Tcr delta(-/-) mice lacking all gamma delta T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr(-)(/-) mice. In both HFD-fed Ldlr(-/-)Il23r(gfp/gfp) and Ldlr(-/-)Tcr delta(-/-) mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators. Conclusions IL-23R(+) gamma delta T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development.