Newell, M. Karen

ABSTRACTCoxsackievirus B3 (CVB3) infection induces myocardial inflammation and myocyte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inherently lack major histocompatibility complex (MHC) class II IE antigen, develop minimal cardiac lesions despite high levels of virus in the heart. The present experiments evaluate the relative roles of class II IA and IE expression on myocarditis susceptibility in four transgenic C57BL/6 mouse strains differing in MHC class II antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA+IE−] and ABo[IA−IE−]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (ABoEα [IA−IE+] and Bl.Tg.Eα [IA+IE+]) had substantial cardiac injury. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positive) cell response in the spleen, while disease resistance correlated to a preferential Th2 (interleukin-4-positive) phenotype. Vγ/Vδ analysis indicates that distinct subpopulations of γδ+T cells are activated after CVB3 infection of C57BL/6 and Bl.Tg.Eα mice. Depletion of γδ+T cells abrogated myocarditis susceptibility in IE+animals and resulted in a Th1→Th2 phenotype shift. These studies indicate that the MHC class II antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of γδ T cells activated during CVB3 infection, and finally that different subpopulations of γδ+T cells may either promote or inhibit Th1 cell responses.

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.