Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Adrenergic receptor ß1-derived peptides act as HLA-DR13-restricted autoantigens and trigger T-helper cell responses in MI patients

N. Hapke1, S. M. Heinrichs1, E. Vogel1, U. Hofmann1, S. Frantz1, G. Ramos2

1Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg; 2Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg;

T-cells are important players in post-myocardial infarction (MI) repair and heart failure (HF) development. In mice, the identification of cardiac epitopes has enabled the development of experimental tools to track heart-specific T-helper cells in vivo. However, the relevant antigen specificities in MI patients remain elusive. Here, we sought to identify such cardiac autoantigens in MI patients with a defined HLA-DR genotype. An initial in silico analysis to simulate HLA-DR1*01:01 restriction of selected cardiac proteins identified 90 potentially relevant cardiac epitopes derived from the cardiac motor proteins and receptors. These were then tested in vitro on human peripheral blood mononuclear cells (PBMCs) obtained from MI patients or from subjects who underwent elective coronary angiography but showed no signs of coronary artery disease (CA group). Interleukin-2- (IL-2) and interferon-g (IFN-g)-producing T-cell counts were monitored by ELISpot as a readout for antigen-specific T helper cell responses. We found that a fraction of MI patients exhibited IFN-g responses when stimulated with a pool of 22 adrenergic receptor beta 1 (ADRB1) derived antigens. Further analyses indicated that two overlapping ADRB1 peptides were sufficient to induce T-cell activation in some MI, but not in CA patients. An HLA-DRB1 genotyping further indicated that only patients that carried at least one allele of the HLA-DR13 family responded to the identified ADRB1 antigens. Interestingly, we found that HLA-DR13 carriers were also enriched in our MI cohort (15/47 patients; 31.9%), as compared to CA controls (9/49 patients; 18.4%). To validate this HLA restriction, PBMCs from HLA-DR13+ and HLA-DR13- healthy donors were cultivated in the presence of the ADRB1 epitopes for 14 days. Again, only HLA-DR13+ PBMCs responded. In conclusion, we identified two HLA-DR13-restricted ADRB1-derived epitopes that can trigger T-helper cell responses in MI patients. These observations will pave the way for tracking antigen-specific CD4+ T cells in HLA-DR13+ MI patients and to mechanistically dissect these cells’ distinct roles in disease progression.

https://dgk.org/kongress_programme/jt2022/aV1048.html