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 language | English (US) |
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Article number | 1076808 |
Journal | Frontiers in Cardiovascular Medicine |
Volume | 9 |
DOIs | |
State | Published - Jan 5 2023 |
Bibliographical note
Funding Information:This work was supported by the Deutsche Forschungsgemeinschaft (NE 2574/1-1 to FSN and WI 4811/1-1 to HW) and the National Institutes of Health (R01 HL121697, P01 HL136275, project 4, core E and HL145241 core to KL).
Publisher Copyright:
Copyright © 2023 Nettersheim, Ghosheh, Winkels, Kobiyama, Durant, Armstrong, Brunel, Roy, Dileepan, Jenkins, Zajonc and Ley.
Keywords
- ApoB
- P6
- atherosclerosis vaccine
- regulatory T cells
- single-cell RNA-sequencing
PubMed: MeSH publication types
- Journal Article