Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B

Takayuki Kimura, Kouji Kobiyama, Holger Winkels, Kevin Tse, Jacqueline Miller, Melanie Vassallo, Dennis Wolf, Christian Ryden, Marco Orecchioni, Thamotharampillai Dileepan, Marc K. Jenkins, Eddie A. James, William W. Kwok, David B. Hanna, Robert C. Kaplan, Howard D. Strickler, Helen G. Durkin, Seble G. Kassaye, Roksana Karim, Phyllis C. TienAlan L. Landay, Stephen J. Gange, John Sidney, Alessandro Sette, Klaus Ley

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1130-1143
Number of pages14
JournalCirculation
Volume138
Issue number11
DOIs
StatePublished - Jan 1 2018

Fingerprint

Apolipoproteins B
Regulatory T-Lymphocytes
Major Histocompatibility Complex
Epitopes
Peptides
T-Lymphocytes
Cardiovascular Diseases
Apolipoproteins E
Immunization
Atherosclerosis
Transcription Factors
Antigens
HLA Antigens
Green Fluorescent Proteins
Tretinoin
LDL Lipoproteins
Carotid Arteries
Interleukin-10
Aorta
Blood Cells

Keywords

  • Antigen specificity
  • ApoB-100
  • Atherosclerosis
  • Regulatory T cells
  • Vaccination

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. / Kimura, Takayuki; Kobiyama, Kouji; Winkels, Holger; Tse, Kevin; Miller, Jacqueline; Vassallo, Melanie; Wolf, Dennis; Ryden, Christian; Orecchioni, Marco; Dileepan, Thamotharampillai; Jenkins, Marc K.; James, Eddie A.; Kwok, William W.; Hanna, David B.; Kaplan, Robert C.; Strickler, Howard D.; Durkin, Helen G.; Kassaye, Seble G.; Karim, Roksana; Tien, Phyllis C.; Landay, Alan L.; Gange, Stephen J.; Sidney, John; Sette, Alessandro; Ley, Klaus.

In: Circulation, Vol. 138, No. 11, 01.01.2018, p. 1130-1143.

Research output: Contribution to journalArticle

Kimura, T, Kobiyama, K, Winkels, H, Tse, K, Miller, J, Vassallo, M, Wolf, D, Ryden, C, Orecchioni, M, Dileepan, T, Jenkins, MK, James, EA, Kwok, WW, Hanna, DB, Kaplan, RC, Strickler, HD, Durkin, HG, Kassaye, SG, Karim, R, Tien, PC, Landay, AL, Gange, SJ, Sidney, J, Sette, A & Ley, K 2018, 'Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B', Circulation, vol. 138, no. 11, pp. 1130-1143. https://doi.org/10.1161/CIRCULATIONAHA.117.031420
Kimura, Takayuki ; Kobiyama, Kouji ; Winkels, Holger ; Tse, Kevin ; Miller, Jacqueline ; Vassallo, Melanie ; Wolf, Dennis ; Ryden, Christian ; Orecchioni, Marco ; Dileepan, Thamotharampillai ; Jenkins, Marc K. ; James, Eddie A. ; Kwok, William W. ; Hanna, David B. ; Kaplan, Robert C. ; Strickler, Howard D. ; Durkin, Helen G. ; Kassaye, Seble G. ; Karim, Roksana ; Tien, Phyllis C. ; Landay, Alan L. ; Gange, Stephen J. ; Sidney, John ; Sette, Alessandro ; Ley, Klaus. / Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. In: Circulation. 2018 ; Vol. 138, No. 11. pp. 1130-1143.
@article{425ee8ec3daf42feb71eef432a6f40c6,
title = "Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B",
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.",
keywords = "Antigen specificity, ApoB-100, Atherosclerosis, Regulatory T cells, Vaccination",
author = "Takayuki Kimura and Kouji Kobiyama and Holger Winkels and Kevin Tse and Jacqueline Miller and Melanie Vassallo and Dennis Wolf and Christian Ryden and Marco Orecchioni and Thamotharampillai Dileepan and Jenkins, {Marc K.} and James, {Eddie A.} and Kwok, {William W.} and Hanna, {David B.} and Kaplan, {Robert C.} and Strickler, {Howard D.} and Durkin, {Helen G.} and Kassaye, {Seble G.} and Roksana Karim and Tien, {Phyllis C.} and Landay, {Alan L.} and Gange, {Stephen J.} and John Sidney and Alessandro Sette and Klaus Ley",
year = "2018",
month = "1",
day = "1",
doi = "10.1161/CIRCULATIONAHA.117.031420",
language = "English (US)",
volume = "138",
pages = "1130--1143",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B

AU - Kimura, Takayuki

AU - Kobiyama, Kouji

AU - Winkels, Holger

AU - Tse, Kevin

AU - Miller, Jacqueline

AU - Vassallo, Melanie

AU - Wolf, Dennis

AU - Ryden, Christian

AU - Orecchioni, Marco

AU - Dileepan, Thamotharampillai

AU - Jenkins, Marc K.

AU - James, Eddie A.

AU - Kwok, William W.

AU - Hanna, David B.

AU - Kaplan, Robert C.

AU - Strickler, Howard D.

AU - Durkin, Helen G.

AU - Kassaye, Seble G.

AU - Karim, Roksana

AU - Tien, Phyllis C.

AU - Landay, Alan L.

AU - Gange, Stephen J.

AU - Sidney, John

AU - Sette, Alessandro

AU - Ley, Klaus

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Antigen specificity

KW - ApoB-100

KW - Atherosclerosis

KW - Regulatory T cells

KW - Vaccination

UR - http://www.scopus.com/inward/record.url?scp=85055597427&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055597427&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.117.031420

DO - 10.1161/CIRCULATIONAHA.117.031420

M3 - Article

C2 - 29588316

AN - SCOPUS:85055597427

VL - 138

SP - 1130

EP - 1143

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 11

ER -