T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia

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. C57B1/6 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 C57B1/6 mice (IA^b+IE-) and transgenic mice, either AB^o, IA^b-IE-; ABEα, IA-IE^k+; or B1.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 B1.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 C57B1/6 mice on the same diet. Conclusions - In mildly hypercholesterolemic C57B1/6 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 C57B1/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.