Takayuki Kimura1, Kouji Kobiyama1, Holger Winkels1, Kevin Tse1, Jacqueline Miller1, Melanie Vassallo1, Dennis Wolf1, Christian Ryden1, Marco Orecchioni1, Thamotharampillai Dileepan2, Marc K Jenkins2, Eddie A James3, William W Kwok3, David B Hanna4, Robert C Kaplan4, Howard D Strickler4, Helen G Durkin5, Seble G Kassaye6, Roksana Karim7, Phyllis C Tien8, Alan L Landay9, Stephen J Gange10, John Sidney11, Alessandro Sette11, Klaus Ley12. 1. Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA (T.K., K.K., H.W., K.T., J.M., M.V., D.W., C.R., M.O., K.L.). 2. Department of Microbiology, University of Minnesota Medical School, Minneapolis (T.D., M.K.J.). 3. Tetramer Core Laboratory, Benaroya Research Institute at Virginia Mason, Seattle, WA (E.A.J., W.W.K.). 4. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (D.B.H., R.C.K., H.D.S.). 5. Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY (H.G.D.). 6. Department of Medicine, Georgetown University, Washington, DC (S.G.K.). 7. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (R.K.). 8. Department of Medicine, University of California, San Francisco (P.C.T.). 9. Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL (A.L.L.). 10. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (S.J.G.). 11. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, CA (J.S., A.S.). 12. Department of Bioengineering, University of California, San Diego, La Jolla (K.L.).
Abstract
BACKGROUND: CD4+ T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules. METHODS: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe-/-) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. RESULTS: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4+ T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe-/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells on vaccination, which were enriched for interleukin-10-producing Tregs. CONCLUSIONS: These findings show that APOB p18-specific CD4+ T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.
BACKGROUND:CD4+ T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a humanAPOBpeptide, p18, that is sequence-identical in mouseApoB and binds to both mouse and human major histocompatibility complex class II molecules. METHODS: We constructed p18 tetramers to detect human and mouseAPOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe-/-)mice were vaccinated with p18peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. RESULTS: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4+ T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe-/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouseI-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells on vaccination, which were enriched for interleukin-10-producing Tregs. CONCLUSIONS: These findings show that APOBp18-specific CD4+ T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoBpeptide 18 as the first Treg epitope in human and mouseatherosclerosis.
Entities:
Keywords:
antigen specificity; apoB-100; atherosclerosis; regulatory T cells; vaccination
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