Single cell transcriptomics and TCR reconstruction reveal CD4 T cell response to MHC-II-restricted APOB epitope in human cardiovascular disease

Atherosclerosis is accompanied by a CD4 T cell response to apolipoprotein B (APOB). Major histocompatibility complex class II (MHC-II) tetramers can be used to isolate antigen-specific CD4 T cells by flow sorting. Here, we produce, validate and use an MHC-II tetramer, DRB1*07:01 APOB-p18, to sort APOB-p18-specific CD4 T cells from peripheral blood mononuclear cell samples from eight DRB1*07:01⁺ women with and without subclinical cardiovascular disease (sCVD). Single-cell RNA sequencing showed that transcriptomes of tetramer-positive cells were between regulatory and memory T cells in healthy women and moved closer to memory T cells in women with sCVD. T cell receptor sequencing of tetramer-positive cells showed clonal expansion and V and J segment usage similar to those found in regulatory T cells. These findings suggest that APOB-specific regulatory T cells may switch to a more memory-like phenotype in women with atherosclerosis. Mouse studies showed that such switched cells promote atherosclerosis.