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. Methods and 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]γ+) 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−; ABEα, IA−IE k +; or Bl.Tg.Eα, IA b +IE k +, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in AB o , ABEα, and Bl.Tg.Eα 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 (α-CD4) or cytokines (IL-4) also caused ≥80% reductions in lesion size. Immunohistology revealed IFN-γ, 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 IFNγ+ Th1 cells in both C57Bl/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.