title: T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia.
abstract: BACKGROUND
  T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia.
  
  
  RESULTS
  BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IA(d), IE(d)) and are atherosclerosis-resistant. C57Bl/6 mice produce a CD4+ Th1 (interferon [IFN]gamma+) response, express IA(b) but no IE, and are atherosclerosis-prone. To evaluate T helper-cell phenotype in fatty streak formation, wild-type C57Bl/6 mice (IA(b)+IE-) and transgenic mice, either AB(o), IA(b)-IE-; ABEalpha, IA-IE(k)+; or BL:TG:Ealpha, IA(b)+IE(k)+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in AB(o), ABEalpha, and BL:TG:Ealpha strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper-cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (alpha-CD4) or cytokines (IL-4) also caused >/=80% reductions in lesion size. Immunohistology revealed IFN-gamma, but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell-deficient) developed aortic lesions comparable to C57Bl/6 mice on the same diet.
  
  
  CONCLUSIONS
  In mildly hypercholesterolemic C57Bl/6 mice, presence of IA(b) and absence of IE regulated CD4+ T helper-cell phenotype; fatty lesions were proportional to IFNgamma+ Th1 cells in both C57Bl/6 and BALB/c strains. IFN-gamma may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.
authors.affiliation: Department of Pathology, University of Vermont, Burlington, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Huber
authors.forename: P
authors.initials: P
authors.lastname: Sakkinen
authors.forename: C
authors.initials: C
authors.lastname: David
authors.forename: M K
authors.initials: MK
authors.lastname: Newell
authors.forename: R P
authors.initials: RP
authors.lastname: Tracy
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006937:Hypercholesterolemia / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D050800:STAT6 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D004041:Dietary Fats; D000949:Histocompatibility Antigens Class II; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D002784:Cholesterol