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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-05-1729.
Submitted May 29, 2003
Accepted August 3, 2003
Specific abrogation of transforming growth factor- signaling in T cells alters atherosclerotic lesion size and composition in mice
Andrea Gojova, Valerie Brun, Bruno Esposito, Francoise Cottrez, Pierre Gourdy, Patrice Ardouin, Alain Tedgui, Ziad Mallat*, and Herve Groux
Institut Federatif de Recherche "Circulation Paris VII," Hopital Lariboisiere, INSERM, Unite 541, Paris, France
TxCell, Bat. ARC, Nice, France
Hopital de l'Archet, INSERM, Unite 343, Nice, France
INSERM, Unite 397, Toulouse, France
Zootechnologie, Institut Gustave Roussy, Villejuif, France
* Corresponding author; email: mallat{at}larib.inserm.fr.
A large body of evidence supports a role for pro-inflammatory 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 (TGF)- . Transgenic mice that express a dominant-negative TGF- receptor type II under a T cell-specific promoter were generated. Bone marrow transplantation from transgenic mice into irradiated low density lipoprotein receptor knockout (LDLr KO) mice, subsequently fed an atherogenic diet, resulted in T-cell specific blockade of TGF- signaling in the recipient mice and increased differentiation of T cells towards both T helper (Th)1 and Th2 phenotypes. These mice showed a significant decrease in atherosclerotic lesion size in the aortic sinus compared with mice transplanted with the wild type bone marrow. Atherosclerotic plaques of mice transplanted with the transgenic bone marrow showed increased T cell infiltration and expression of major histocompatability (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- signaling in atherosclerosis.
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