Published online before print January 19, 2006, doi: 10.1161/01.RES.0000204452.46568.57
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Submitted on May 25, 2005
Revised on December 28, 2005
Accepted on January 5, 2006
Interleukin 12 Induces T-Cell Recruitment Into the Atherosclerotic Plaque
Xiaoyu Zhang ;
From the Department of Medicine (X.Z., A.N., W.M.-K., J.J.G., C.M.W.), Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Ga; Divison of Periodontology (T.N.), Niigata University Graduate School of Medical and Dental Sciences, Japan; and Division of Cardiovascular Disease (S.L.K., R.L.F.), Mayo Clinic, Rochester, Minn.
* To whom correspondence should be addressed. E-mail: cweyand{at}emory.edu.
CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4+CD28- T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4+CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4+CD28- IL-12R+ cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4+CD28- T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4+CD28- T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4+CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4+CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.
Key words: inflammation • interleukins • cytokines • T lymphocyte • vascular inflammation
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