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

Li, Jie; McArdle, Sara; Gholami, Amin; Kimura, Takayuki; Wolf, Dennis; Gerhardt, Teresa; Miller, Jacqueline; Weber, Christian und Ley, Klaus (2016): CCR5⁺T-bet⁺FoxP3⁺ Effector CD4 T Cells Drive Atherosclerosis. In: Circulation Research, Bd. 118, Nr. 10: 1540-U213

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-gamma 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-gamma, 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0009-7330
• Sprache: Englisch