P288	Natural CD4+CD25+ regulatory T cells control the development of atherosclerosis in mice.
1H.Ait Oufella, 1S.Potteaux, 2B.Salomon, 3P.Gourdy, 1B.Esposito, 2D.Klatzmann, 1A.Tedgui, 1Z.Mallat
1Inserm U689, Paris, FR; 2CNRS 7087, Paris, FR; 3Inserm U589, Toulouse, FR.

Introduction : Th1-lymphocytes play a pathogenic role in atherosclerosis. In addition, Th2 immune reponses do not invariably protect from lesion development. A specific component of the immune system, known as the CD4+CD25+ regulatory T cell subset, is specialized in the suppression of both Th1 and Th2 pathogenic immune reponses against self and non-self antigen and controls T cell homeostasis.We have investigated the role of this Treg subpopulation in the development of atherosclerosis. Methods and results: CD28 deficiency leads to a profound reduction in Treg cells. We first examined the effect of Treg deficiency (using CD28 deficient cells) on the development of atherosclerosis in apoE-/-/RAG2-/- mice. We compared a group of mice injected with wild type splenocytes (10 millions cells intravenously) with another group injected with Treg-poor CD28-deficient splenocytes (10 millions cells). Interestingly, after 6 weeks of high fat diet, lesion size more than doubled (+167%, P=0.012) in apoE-/-/RAG2-/- mice transferred with CD28-deficient splenocytes compared to control splenocytes. To examine whether CD4+CD25+ Treg cell deficiency was directly responsible for the enhancement of lesion development in a CD28-deficient context, another group of apoE-/-/RAG2-/- mice injected with 10 millions CD28-deficient splenocytes was co-transferred with 1 million CD4+CD25+ Treg cells . Co-transfer of CD4+CD25+ Treg cells abrogated the induction of atherosclerosis induced by CD28-deficient splenocytes (-51%, P=0.02). In addition, co-transfer of Treg resulted in a marked reduction of plaque T cell content (-82%, P<0.05) and macrophage infiltration (-35%,P<0.05) with a significant increase of collagen accumulation (+58%, P<0.05), suggesting reduced plaque inflammation and increased plaque healing. The transferred Treg cells were recovered using specific magnetic beads, they survived in vivo and retained a high level of FOXP3 mRNA expression. Co-culture studies showed that the transferred Treg cells were able to inhibit CD4+CD25- cells proliferation in vitro, through a TGF-β-dependent and cell-cell contact mechanism. Conclusion: CD4+CD25+ regulatory T cells control the development of atherosclerosis in mice.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.