title: γδT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.
abstract: Unique innate immunity-linked γδT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether γδT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that γδT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild-type 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. γδT 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 γδT cells produced IL-17, but not IFN-γ, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic γδT cells in individual ApoE KO mice. To investigate the role of these γδT cells in early atherogenesis, we analyzed ApoE/γδT 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/γδT 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 γδT cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting γδT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Vu
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Tai
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Tatro
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Brigitte T
authors.initials: BT
authors.lastname: Huber
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Debbie
authors.initials: D
authors.lastname: Beasley
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications / Q000473:pathology*; D020381:Interleukin-17 / Q000378:metabolism; D007960:Leukocyte Disorders / Q000209:etiology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D004549:Elastin; D020381:Interleukin-17; D008055:Lipids; D016692:Receptors, Antigen, T-Cell, gamma-delta; C067980:CD68 antigen, human; D000097382:CD68 Molecule