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(Circulation Research. 2006;98:524.)
© 2006 American Heart Association, Inc.

Cellular Biology

Interleukin 12 Induces T-Cell Recruitment Into the Atherosclerotic Plaque

Xiaoyu Zhang^*, Alexander Niessner^*, Takako Nakajima, Wei Ma-Krupa, Stephen L. Kopecky, Robert L. Frye, Jörg J. Goronzy, Cornelia M. Weyand

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.

Correspondence to Cornelia M. Weyand, MD, PhD, Lowance Center for Human Immunology, Emory University, 101 Woodruff Circle, Atlanta, GA 30322. 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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Antigen-Independent Targeting of Long-Lived CD4⁺ Cytolytic T Effector Cells to Lesions of Atherosclerosis

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