Regulatory CD4(+) T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B.
Regulatory CD4(+) T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B.
复制标题
DOI：
10.1161/circulationaha.117.031420
复制
发表时间：
2018-09-11
期刊：
影响因子：
37.8
通讯作者：
Ley K
中科院分区：
文献类型：
--
作者：
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
CD 4 + T细胞在动脉粥样硬化中起重要作用，但其抗原特异性知之甚少。已知用载脂蛋白B（Apo B，低密度脂蛋白的核心蛋白）免疫在动物模型中具有动脉粥样硬化保护作用。在这里，我们报告的人类APOB肽，p18，这是在小鼠ApoB序列相同，并结合到小鼠和人类MHC-II。我们构建了p18-四聚体来检测人和小鼠APOB特异性T细胞，并通过流式细胞术分析其表型，包括CD 4谱系转录因子，细胞内细胞因子和TCR活化。Apoe−/−小鼠单独接种p18肽或佐剂，并测定主动脉中的动脉粥样硬化负荷。在来自无心血管疾病（CVD）供体的人外周血单个核细胞中，用新的HLA-DR-p18四聚体检测到的p18特异性CD 4 + T细胞主要是Foxp 3+调节性T细胞（TcR）。经颈动脉超声检查发现亚临床CVD的供者有TcR共表达的RORγt或T-bet，而无CVD的供者几乎不表达这两种蛋白。在Apoe−/−小鼠中，用p18免疫诱导了Tcirrhosis并减少了动脉粥样硬化病变。在肽再刺激后，通过Nur 77-GFP鉴定的应答性CD 4 + T细胞在TCF 3中高度富集。一种新的小鼠I-Ab-p18四聚体鉴定了疫苗接种后p18特异性CD 4 + T细胞的扩增，这些细胞富含产生IL-10的T细胞。这些发现表明，APOB p18特异性CD 4 + T细胞在健康供体中主要是TcB，但在亚临床CVD供体中共表达其他CD 4谱系转录因子。本研究鉴定了ApoB肽18作为人和小鼠动脉粥样硬化中的第一个Treg表位。
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 MHC-II. 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 TCR activation. Apoe−/− mice were vaccinated with p18 peptide or adjuvants alone and atherosclerotic burden in the aorta was determined. In human peripheral blood mononuclear cells from donors without cardiovascular disease (CVD), p18 specific CD4+ T cells detected by a new HLA-DR-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical CVD as detected by carotid artery ultrasound had Tregs co-expressing RORγt or T-bet which were both almost absent in donors without CVD. In Apoe−/− mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP were highly enriched in Tregs. A new mouse I-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells upon vaccination, which were enriched for IL-10-producing Tregs. These findings show that APOB p18 specific CD4+ T cells are mainly Tregs in healthy donors, but co-express other CD4 lineage transcription factors in donors with subclinical CVD. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.