Published Online
on May 8, 2006

A more recent version of this article appeared on May 16, 2006

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Submitted on December 9, 2005
Revised on March 6, 2006
Accepted on March 9, 2006

Chemokine CXCL10 Promotes Atherogenesis by Modulating the Local Balance of Effector and Regulatory T Cells

Eric A. Heller MD, Emerson Liu MD, Andrew M. Tager MD, Qian Yuan MD, Alexander Y. Lin MD, Neil Ahluwalia BS, Krister Jones BA, Stephanie L. Koehn BS, Vincent M. Lok BA, Elena Aikawa MD, PhD, Kathryn J. Moore PhD, Andrew D. Luster MD, PhD, and Robert E. Gerszten MD^*

From the Center for Immunology and Inflammatory Diseases (E.A.H., E.L., A.M.T., Q.Y., A.Y.L., N.A., K.J., A.D.L., R.E.G.), Cardiovascular Research Center (E.A.H., E.L., A.Y.L., N.A., R.E.G.), and Center for Molecular Imaging Research (V.M.L., E.A.), Massachusetts General Hospital, Charlestown, Mass, and Harvard Medical School, Boston, Mass; and Lipid Metabolism Unit & Endocrine Division (S.L.K., K.J.M.), Massachusetts General Hospital, Boston, Mass, and Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: rgerszten{at}partners.org.

Background--Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis.

Methods and Results--Compound deficient Apoe^-/-/Cxcl10^-/- mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe^-/- controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4⁺ T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (T_reg) numbers and activity were enhanced, as assessed by increased message for the T_reg-specific marker Foxp3, as well as increases in immunostaining for the T_reg-associated cytokines interleukin-10 and transforming growth factor-1. We also documented naturally occurring T_reg cells in human atherosclerotic lesions.

Conclusions--We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.

Key words: atherosclerosis • immunology • inflammation • leukocytes • chemokines

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