Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells.
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.


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 (Treg) numbers and activity were enhanced, as assessed by increased message for the Treg-specific marker Foxp3, as well as increases in immunostaining for the Treg-associated cytokines interleukin-10 and transforming growth factor-beta1. We also documented naturally occurring Treg 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.
Heller
Eric A
EA
Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Liu
Emerson
E
Tager
Andrew M
AM
Yuan
Qian
Q
Lin
Alexander Y
AY
Ahluwalia
Neil
N
Jones
Krister
K
Koehn
Stephanie L
SL
Lok
Vincent M
VM
Aikawa
Elena
E
Moore
Kathryn J
KJ
Luster
Andrew D
AD
Gerszten
Robert E
RE