Single-cell transcriptomes and T cell receptors of vaccine-expanded apolipoprotein B-specific T cells

Felix Sebastian Nettersheim, Yanal Ghosheh, Holger Winkels, Kouji Kobiyama, Christopher Durant, Sujit Silas Armstrong, Simon Brunel, Payel Roy, Thamotharampillai Dileepan, Marc K. Jenkins, Dirk M. Zajonc, Klaus Ley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1076808
JournalFrontiers in Cardiovascular Medicine
Volume9
DOIs
StatePublished - Jan 5 2023

Keywords

  • ApoB
  • P6
  • atherosclerosis vaccine
  • regulatory T cells
  • single-cell RNA-sequencing

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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