Format

Send to

Choose Destination
Circ Res. 2016 May 13;118(10):1540-52. doi: 10.1161/CIRCRESAHA.116.308648. Epub 2016 Mar 28.

CCR5+T-bet+FoxP3+ Effector CD4 T Cells Drive Atherosclerosis.

Author information

1
From the Division of Inflammation Biology (J.L., S.M., T.K., D.W., T.G., J.M., K.L.) and Bioinformatics Core (A.G.), La Jolla Institute for Allergy & Immunology, CA; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.W.).
2
From the Division of Inflammation Biology (J.L., S.M., T.K., D.W., T.G., J.M., K.L.) and Bioinformatics Core (A.G.), La Jolla Institute for Allergy & Immunology, CA; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.W.). klaus@liai.org.

Abstract

RATIONALE:

CD4 T cells are involved in the pathogenesis of atherosclerosis, but atherosclerosis-specific CD4 T cells have not been described. Moreover, the chemokine(s) that regulates T-cell trafficking to the atherosclerotic lesions is also unknown.

OBJECTIVE:

In Apoe(-/-) mice with mature atherosclerotic lesions (5 months of high fat diet), we find that most aortic T cells express CCR5 and interferon-γ with a unique combination of cell surface markers (CD4(+)CD25(-)CD44(hi)CD62L(lo)) and transcription factors (FoxP3(+)T-bet(+)). We call these cells CCR5Teff. We investigated the role of CCR5 in regulating T-cell homing to the atherosclerotic aorta and the functionality of the CCR5Teff cells.

METHODS AND RESULTS:

CCR5Teff cells are exclusively found in the aorta and para-aortic lymph nodes of Apoe(-/-) mice. They do not suppress T-cell proliferation in vitro and are less potent than regulatory T cells at inhibiting cytokine secretion. Blocking or knocking out CCR5 or its ligand CCL5 significantly blocks T-cell homing to atherosclerotic aortas. Transcriptomic analysis shows that CCR5Teff cells are more similar to effector T cells than to regulatory T cells. They secrete interferon-γ, interleukin-2, interleukin-10, and tumor necrosis factor. Adoptive transfer of these CCR5Teff cells significantly increases atherosclerosis.

CONCLUSIONS:

CCR5 is specifically needed for CD4 T-cell homing to the atherosclerotic plaques. CCR5(+)CD4 T cells express an unusual combination of transcription factors, FoxP3 and T-bet. Although CCR5Teff express FoxP3, we showed that they are not regulatory and adoptive transfer of these cells exacerbates atherosclerosis.

KEYWORDS:

CCR5 protein, mouse; Ccl5 protein, mouse; Treg cells; atherosclerosis; chemokines; inflammation; vascular diseases

PMID:
27021296
PMCID:
PMC4867125
DOI:
10.1161/CIRCRESAHA.116.308648
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center