Specific abrogation of transforming growth factor-beta signaling in T cells alters atherosclerotic lesion size and composition in mice.
A large body of evidence supports a role for proinflammatory mediators in atherosclerotic disease progression and instability. However, only few endogenous mechanisms have been suggested that could alter disease progression. One such mechanism is thought to be mediated by transforming growth factor beta (TGF-beta). Transgenic mice that express a dominant-negative TGF-beta receptor type II under a T-cell-specific promoter were generated. Bone marrow transplantation from transgenic mice into irradiated low density lipoprotein receptor knock-out (LDLr KO) mice, subsequently fed an atherogenic diet, resulted in T-cell-specific blockade of TGF-beta signaling in the recipient mice and increased differentiation of T cells toward both T helper 1 (Th1) and Th2 phenotypes. These mice showed a significant decrease in atherosclerotic lesion size in the aortic sinus compared with mice receiving transplants with the wild-type bone marrow. Atherosclerotic plaques of mice receiving transplants with the transgenic bone marrow showed increased T-cell infiltration and expression of major histocompatability complex (MHC) class II, along with a decrease in smooth muscle cell and collagen content, a plaque phenotype that is potentially vulnerable to rupture. These results identify for the first time an important role for specific and selective T-cell-TGF-beta signaling in atherosclerosis.
Gojova
Andrea
A
INSERM U541, Hôpital Lariboisière, 41 Bd de la chapelle, 75010 Paris, France.
Brun
Valérie
V
Esposito
Bruno
B
Cottrez
Françoise
F
Gourdy
Pierre
P
Ardouin
Patrice
P
Tedgui
Alain
A
Mallat
Ziad
Z
Groux
Hervé
H
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D004036:Diet, Atherogenic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011973:Receptors, LDL / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018417:Th1 Cells; D018418:Th2 Cells; D016212:Transforming Growth Factor beta / Q000502:physiology*
D011973:Receptors, LDL; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II