T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery

• DOI: 10.1126/sciadv.adk3060
• Publication Date: 2024-02-02T18:58:50Z
• Authors: Miray Cetin; Veronica Pinamonti; Theresa Schmid; Tamara Boschert; Ana Mellado Fuentes; Kristina Kromer; Taga Lerner; Jing Zhang; Yonatan Herzig; Christopher Ehlert; Miguel Hernandez-...; Georgios Samaras; Claudia Maldonado...; Laura Fisch; Valeriia Dragan; Arlette Kouwenhoven; Bertrand Van Scho...; Hans Wils; Carl Van Hove; Michael Platten; Edward W. Green; Frederik Stevenaert; Nathan J. Felix; John M. Lindner
• Keywords: 0301 basic medicine; 03 medical and health sciences; HLA Antigens; Histocompatibility Antigens Class I; Receptors, Antigen, T-Cell; Histocompatibility Antigens Class II; Humans; Biomedicine and Life Sciences; Ligands

Effective, unbiased, high-throughput methods to functionally identify both class II and I HLA-presented T cell epitopes their cognate receptors (TCRs) are essential for prerequisite diagnostic therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T Functional Identification (Neo)-antigen Discovery of Epitopes Receptors], a system rapidly deconvolute CD4 CD8 TCRs targets physiologically processed presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining highly sensitive TCR signaling reporter with processing overcome previously undescribed limitations target expression, robustly identifies unknown peptide:HLA ligands from libraries screens validates the specificity large against known or predicted targets. To demonstrate its capabilities, apply platform multiple TCR-based including diffuse midline glioma, celiac disease, rheumatoid arthritis, providing unique biological insights showcasing T-FINDER's potency versatility.