Single-cell transcriptomes and T cell receptors of vaccine-expanded apolipoprotein B-specific T cells.
Single-cell transcriptomes and T cell receptors of vaccine-expanded apolipoprotein B-specific T cells.
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DOI：
10.3389/fcvm.2022.1076808
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发表时间：
2022
影响因子：
3.6
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中科院分区：
文献类型：
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动脉粥样硬化性心血管疾病是世界范围内死亡的主要原因。载脂蛋白B(ApoB)是大多数脂蛋白的核心蛋白，CD4T细胞对载脂蛋白B的反应被认为是重要的疾病调节因子。在健康人中，载脂蛋白B反应(ApoB+)的CD4T细胞主要是调节性T细胞(Tregs)，发挥抗炎作用。然而，它们可能获得促炎功能，从而成为致动脉粥样硬化的因素。来自动物研究的证据表明，接种某些主要组织相容性复合体(MHC)II结合的ApoB多肽可以诱导ApoB+Tregs的扩张，从而提供动脉粥样硬化保护。到目前为止，还没有对疫苗扩增的ApoB+T细胞进行深入的表型鉴定。为此，我们用ApoB多肽P6(ApoB978-993TGAYSNASSTESASY)免疫C57BL/6J小鼠，并对四聚体分选的P6+T细胞进行了单细胞RNA测序。P6+细胞克隆扩增(一个大克隆，两个小克隆)，形成一个转录簇，与主要包含未扩增的P6+和P6-细胞的簇不同。转录图谱显示，大多数扩增的P6+细胞具有强烈的Treg信号，并高表达介导抑制功能的基因。然而，一些扩增的P6+细胞只有残留的Treg信号，并表达与Thelper 1(TH1)细胞相关的基因，这是导致动脉粥样硬化的因素。对T细胞受体和P6：MHC-II相互作用的模拟表明，α和β链上只有三个氨基酸残基与MHC-II沟中的P6肽接触，从而决定了该T细胞受体对P6的特异性。我们的数据开始揭示疫苗接种后对载脂蛋白B表位的反应。
Atherosclerotic cardiovascular diseases are the major cause of death worldwide. CD4 T cells responding to Apolipoprotein B (ApoB), the core protein of most lipoproteins, have been identified as critical disease modulators. In healthy individuals, ApoB-reactive (ApoB+) CD4 T cells are mostly regulatory T cells (Tregs), which exert anti-inflammatory effects. Yet, they may obtain pro-inflammatory features and thus become proatherogenic. Evidence from animal studies suggests that vaccination against certain major histocompatibility complex (MHC) II-binding ApoB peptides induces an expansion of ApoB+ Tregs and thus confers atheroprotection. To date, in-depth phenotyping of vaccine-expanded ApoB+ T cells has not yet been performed. To this end, we vaccinated C57BL/6J mice with the ApoB-peptide P6 (ApoB978–993 TGAYSNASSTESASY) and performed single-cell RNA sequencing of tetramer-sorted P6+ T cells. P6+ cells were clonally expanded (one major, two minor clones) and formed a transcriptional cluster distinct from clusters mainly containing non-expanded P6+ and P6– cells. Transcriptomic profiling revealed that most expanded P6+ cells had a strong Treg signature and highly expressed genes mediating suppressive functions. Yet, some expanded P6+ cells only had a residual Treg signature and expressed genes related to T helper 1 (TH1) cells, which are proatherogenic. Modeling the T cell receptor (TCR) and P6:MHC-II interaction showed that only three amino acid residues in the α and β chain contact the P6 peptide in the MHC-II groove and thus determine the specificity of this TCR to P6. Our data begin to reveal the vaccination-induced response to an ApoB epitope.