Disruption of TGF-beta signaling in T cells accelerates atherosclerosis.
Increasing evidence suggests that atherosclerosis is an inflammatory disease promoted by hypercholesterolemia. The role of adaptive immunity has been controversial, however. We hypothesized that proatherogenic T cells are controlled by immunoregulatory cytokines. Among them, TGF-beta has been implied in atherosclerosis, but its mechanism of action remains unclear. We crossed atherosclerosis-prone ApoE-knockout mice with transgenic mice carrying a dominant negative TGF-beta receptor II in T cells. The ApoE-knockout mice with disrupted TGF-beta signaling in T cells exhibited a sixfold increase in aortic lesion surface area, a threefold increase in aortic root lesion size, and a 125-fold increase in aortic IFN-gamma mRNA when compared with age-matched ApoE-knockout littermates. When comparing size-matched lesions, those of mice with T cell-specific blockade of TGF-beta signaling displayed increased T cells, activated macrophages, and reduced collagen, consistent with a more vulnerable phenotype. Ab's to oxidized LDL, circulating T cell cytokines, and spleen T cell activity were all increased in ApoE-knockout mice with dominant negative TGF-beta receptors in T cells. Taken together, these results show that abrogation of TGF-beta signaling in T cells increases atherosclerosis and suggest that TGF-beta reduces atherosclerosis by dampening T cell activation. Inhibition of T cell activation may therefore represent a strategy for antiatherosclerotic therapy.
Robertson
Anna-Karin L
AK
Center for Molecular Medicine, L8:03 Karolinska Hospital, SE-17176 Stockholm, Sweden. Goran.Hansson@cmm.ki.se
Rudling
Mats
M
Zhou
Xinghua
X
Gorelik
Leonid
L
Flavell
Richard A
RA
Hansson
Göran K
GK
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D001057:Apolipoproteins E; D016207:Cytokines; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma