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

Vu DM, Tai A, Tatro JB, Karas RH, Huber BT, Beasley D - PLoS ONE (2014)

Bottom Line: These aortic γδT cells produced IL-17, but not IFN-γ, analyzed by ex vivo FACS.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.Targeting γδT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.

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.

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γδT cell deficiency reduces aortic root lesion area in 24 wk-old chow-fed ApoE KO mice.A&D: Aortic root lipid-rich lesions outlined in green (en face view) are significantly decreased in ApoE/γδT DKO mice (p<0.0001). Lesion area was not affected by γδT cell deficiency in the aortic arch (B&E) or descending aorta (C&F).
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pone-0109416-g004: γδT cell deficiency reduces aortic root lesion area in 24 wk-old chow-fed ApoE KO mice.A&D: Aortic root lipid-rich lesions outlined in green (en face view) are significantly decreased in ApoE/γδT DKO mice (p<0.0001). Lesion area was not affected by γδT cell deficiency in the aortic arch (B&E) or descending aorta (C&F).

Mentions: To determine whether γδT cells affect lesion development in the aortic root or arch, we generated γδT cell-deficient ApoE KO mice (DKO). γδT cells were not detectable by FACS analysis in blood, aorta, spleen or lymph nodes of chow-fed ApoE/TCRδ DKO mice (Fig. S1A and not shown), confirming the γδT cell-deficient phenotype. γδT cell-deficiency reduced lipid-rich en face lesion area by 40% in the aortic root (Fig. 4A; p<0.0001), the site of most active lesion progression in 24 wk-old chow-fed mice. Lesions were infrequent in aortic arch and descending aorta at this early age and stage of disease, and effects of γδT cell deficiency were not detected (Fig. 4B&C). γδT cell deficiency did not affect body weight, spleen weight, or serum triglyceride, but did increase total serum cholesterol in chow-fed ApoE KO mice (Table 2), indicating that γδT cell-deficiency reduced aortic root lesions in chow-fed mice, despite the concurrent increase in serum cholesterol.


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

Vu DM, Tai A, Tatro JB, Karas RH, Huber BT, Beasley D - PLoS ONE (2014)

γδT cell deficiency reduces aortic root lesion area in 24 wk-old chow-fed ApoE KO mice.A&D: Aortic root lipid-rich lesions outlined in green (en face view) are significantly decreased in ApoE/γδT DKO mice (p<0.0001). Lesion area was not affected by γδT cell deficiency in the aortic arch (B&E) or descending aorta (C&F).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4196850&req=5

pone-0109416-g004: γδT cell deficiency reduces aortic root lesion area in 24 wk-old chow-fed ApoE KO mice.A&D: Aortic root lipid-rich lesions outlined in green (en face view) are significantly decreased in ApoE/γδT DKO mice (p<0.0001). Lesion area was not affected by γδT cell deficiency in the aortic arch (B&E) or descending aorta (C&F).
Mentions: To determine whether γδT cells affect lesion development in the aortic root or arch, we generated γδT cell-deficient ApoE KO mice (DKO). γδT cells were not detectable by FACS analysis in blood, aorta, spleen or lymph nodes of chow-fed ApoE/TCRδ DKO mice (Fig. S1A and not shown), confirming the γδT cell-deficient phenotype. γδT cell-deficiency reduced lipid-rich en face lesion area by 40% in the aortic root (Fig. 4A; p<0.0001), the site of most active lesion progression in 24 wk-old chow-fed mice. Lesions were infrequent in aortic arch and descending aorta at this early age and stage of disease, and effects of γδT cell deficiency were not detected (Fig. 4B&C). γδT cell deficiency did not affect body weight, spleen weight, or serum triglyceride, but did increase total serum cholesterol in chow-fed ApoE KO mice (Table 2), indicating that γδT cell-deficiency reduced aortic root lesions in chow-fed mice, despite the concurrent increase in serum cholesterol.

Bottom Line: These aortic γδT cells produced IL-17, but not IFN-γ, analyzed by ex vivo FACS.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.Targeting γδT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus