title: Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells.
abstract: Although immunization with major histocompatibility complex (MHC) class II-restricted apolipoprotein B (ApoB) peptides has been shown to be atheroprotective, the mechanism is unclear. Here, we investigated CD4+T cell populations in immunized atherosclerotic mice. Peptides (16-mers) from mouse ApoB, the core protein of low-density lipoprotein (LDL), were screened for binding to I-Abby computer prediction and confirmed by radiolabeled peptide competition. Three new peptides, P101 (FGKQGFFPDSVNKALY, 5.5 nM IC50), P102 (TLYALSHAVNSYFDVD, 6.8 nM), and P103 (LYYKEDKTSLSASAAS, 95 nM), were tested in an atherosclerosis model (Apoe-/-mice on Western diet). Immunization with each of the three peptides (1 time in complete Freund's adjuvant subcuntaneously and 4 time in incomplete Freund's adjuvant intraperitoneally) but not with adjuvant alone showed significantly reduced atherosclerotic plaques in the aortic root by serial sections and in the whole aorta by en face staining. There were no differences in body weight, LDL cholesterol, or triglycerides. Peritoneal leukocytes from ApoB peptide-immunized mice, but not control mice, secreted significant amounts of IL-10 (150 pg/ml). Flow cytometry showed that peptide immunization induced IL-10 in 10% of peritoneal CD4+T cells, some of which also expressed chemokine (C-C motif) receptor 5 (CCR5). Vaccination with ApoB peptides expanded peritoneal FoxP3+regulatory CD4+T cells and more than tripled the number of CCR5+FoxP3+cells. Similar trends were also seen in the draining mediastinal lymph nodes but not in the nondraining inguinal lymph nodes. We conclude that vaccination with MHC class II-restricted autologous ApoB peptides induces regulatory T cells (Tregs) and IL-10, suggesting a plausible mechanism for atheroprotection.NEW & NOTEWORTHYVaccination against apolipoprotein B (ApoB), the protein of LDL, attracts attention as a novel approach to prevent atherosclerosis. We discovered major histocompatibility complex class II-restricted ApoB peptides, which reduce atherosclerosis and induce IL-10-producing CD4+T cells and chemokine (C-C motif) receptor 5 expression on regulatory T cells, suggesting that immunization with ApoB peptides inhibits atherosclerosis by inducing anti-inflammatory cytokines.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tse
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Sara
authors.initials: S
authors.lastname: McArdle
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gerhardt
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Miller
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Mikulski
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California; and klaus@lji.org.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000276:immunology*; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005802:Genes, MHC Class II / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D014611:Vaccination
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D010455:Peptides; D016753:Interleukin-10
keywords: CCR5; FoxP3; IL-10; MHC class II; apolipoprotein B-100; atherosclerosis; immunization