Jie Li1, Sara McArdle1, Amin Gholami1, Takayuki Kimura1, Dennis Wolf1, Teresa Gerhardt1, Jacqueline Miller1, Christian Weber1, Klaus Ley2. 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.
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.
Authors: Elena Galkina; Brian L Harry; Andreas Ludwig; Elisa A Liehn; John M Sanders; Anthony Bruce; Christian Weber; Klaus Ley Journal: Circulation Date: 2007-10-01 Impact factor: 29.690
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