title: CCR5+T-bet+FoxP3+ Effector CD4 T Cells Drive Atherosclerosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.).
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Sara
authors.initials: S
authors.lastname: McArdle
authors.affiliation: 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.).
authors.forename: Amin
authors.initials: A
authors.lastname: Gholami
authors.affiliation: 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.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kimura
authors.affiliation: 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.).
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.affiliation: 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.).
authors.forename: Teresa
authors.initials: T
authors.lastname: Gerhardt
authors.affiliation: 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.).
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Miller
authors.affiliation: 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.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D001057:Apolipoproteins E; C000592874:CCR5 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D019713:Receptors, CCR5; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019041:L-Selectin; D007371:Interferon-gamma
keywords: CCR5 protein, mouse; Ccl5 protein, mouse; Treg cells; atherosclerosis; chemokines; inflammation; vascular diseases