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Restricted T-Cell Repertoire in the Epicardial Adipose Tissue of Non-ST Segment Elevation Myocardial Infarction Patients

2022; Frontiers Media; Volume: 13; Linguagem: Inglês

10.3389/fimmu.2022.845526

1664-3224

Daniela Pedicino, Anna Severino, Gabriele Di Sante, Maria Cristina De Rosa, Davide Pirolli, Ramona Vinci, Vincenzo Pazzano, Ada Francesca Giglio, Francesco Trotta, Giulio Russo, Aureliano Ruggio, Eugenia Pisano, Alessia d’Aiello, Francesco Canonico, Pellegrino Ciampi, Domenico Cianflone, Lorenzo Cianfanelli, Maria Chiara Grimaldi, Simone Filomia, Nicola Luciani, Franco Glieca, Piergiorgio Bruno, Massimo Massetti, Francesco Ria, Filippo Crea, Giovanna Liuzzo,

Adipokines, Inflammation, and Metabolic Diseases

Aims Human epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression. Methods and Results We enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS ( P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences. Conclusions Our study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.