P287	Depletion of natural CD4+CD25+ regulatory T cells enhances the development of atherosclerosis.
1H.Ait Oufella, 1S.Potteaux, 2B.Salomon, 3A-K.Robertson, 2D.Klatzmann, 3G.Hansson, 1A.Tedgui, 1Z.Mallat
1Inserm U689, Paris, FR; 2CNRS 7087, Paris, FR; 3Karolinska Institute, Stockholm, SE.

Introduction : Immune responses mediated by Th1 cell type promote atherosclerosis development. However, whether immune regulatory responses affect atherosclerosis is unknown. A specific T cell subpopulation, called the natural CD4+CD25+ regulatory cells (Treg) controls the proliferation/activation of pathogenic T cells, in part through membrane TGFb, and inhibits the development of immune and inflammatory diseases. We examined the role of this natural Treg susbset in atherogenesis. Methods and results : 6-week old apoE-/- mice have been depleted in CD4+CD25+ cells by intraperitoneal injections of either anti-CD25 antibody (100µg) or isotype-matched control antibody (IgG) at day 0 and day 30. The mice were sacrified 4 weeks following the second antibody injection. Treatment with anti-CD25 antibody induced 90% reduction in CD25+ cells (lymph nodes, spleen) 14 days after a single injection and more than 75% reduction at day 30, indicating an important and sustained CD25 depletion. Compared to plaque of animals treated with IgG control, anti-CD25 treatment induced a significant increase in atherosclerotic lesion size in the aortic sinus (+48%, P=0.02) pointing to a substantial role for CD4+CD25+ Treg cells in the control of plaque development. Moreover, depletion of Treg was associated with a substantial decrease in collagen accumulation (-57%, P=0.01), and an increase in infiltrating macrophages (+37%, P=0.04) and T lymphocytes (+67%, P=0.02). Interestingly, anti-CD25 treatment of apoE-/- mice expressing a negative dominant TGF-β type II receptor under the control of the CD4 promoter (whose T cells are unresponsive to TGF-β-suppressive effects) had no effect on lesion size or plaque composition. Conclusion : These results show that natural CD4+CD25+ regulatory T cells control plaque development and inflammation. Their regulatory activity seems to be dependent on T cell-TGF-β activity.

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