γδT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice

Abstract

Unique innate immunity-linked cdT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether cdT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that cdT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wildtype mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion progression is most rapid. cdT cells infiltrated intimal lesions in ApoE KO mice, but only the adventitia in wild-type mice, and were more prevalent than CD4+ T cells in early nascent lesions, as evaluated by en face confocal microscopy. These aortic cdT cells produced IL-17, but not IFN-c, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic cdT cells in individual ApoE KO mice. To investigate the role of these cdT cells in early atherogenesis, we analyzed ApoE/cdT double knockout (DKO) compared to ApoE KO mice. We observed reduced early intimal lipid accumulation at sites of nascent lesion formation, both in chow-fed (by 40%) and Western diet-fed (by 44%) ApoE/cdT DKO mice. In addition, circulating neutrophils were drastically reduced in these DKO mice on Western diet, while expansion of inflammatory monocytes and splenic Th1 or Th17 lymphocytes was not affected. These data reveal, for the first time, a pathogenic role of cdT cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting cdT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.