Abstract

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

Li J, McArdle S, Gholami A, Kimura T, Wolf D, Gerhardt T, Miller J, Weber C, Ley K
Circ Res. 2016;118:1540-52

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-? 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-?, 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.

Circ Res. 2016;118:1540-52