CRISPR-Cas9 screening reveals a distinct class of MHC-I binders with precise HLA-peptide recognition
Tom A.W. Schoufour,
Anneloes van der Plas - van Duijn,
Ian Derksen,
Marije Melgers,
Jacqueline M.F. van Veenendaal,
Claire Lensen,
Mirjam H.M. Heemskerk,
Jacques Neefjes,
Ruud H.M. Wijdeven,
Ferenc A. Scheeren
Affiliations
Tom A.W. Schoufour
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Anneloes van der Plas - van Duijn
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands; Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Ian Derksen
Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Marije Melgers
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Jacqueline M.F. van Veenendaal
Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Claire Lensen
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Mirjam H.M. Heemskerk
Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Jacques Neefjes
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands
Ruud H.M. Wijdeven
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit Medical Center, 1007 MB Amsterdam, Noord-Holland, the Netherlands
Ferenc A. Scheeren
Department of Dermatology, Leiden University Medical Center, 2333 ZA Leiden, Zuid-Holland, the Netherlands; Corresponding author
Summary: Human leukocyte antigen (HLA) class-I molecules present fragments of the cellular proteome to the T cell receptor (TCR) of cytotoxic T cells to control infectious diseases and cancer. The large number of combinations of HLA class-I allotypes and peptides allows for highly specific and dedicated low-affinity interactions to a diverse array of TCRs and natural killer (NK) cell receptors. Whether the divergent HLA class-I peptide complex is exclusive for interactions with these proteins is unknown. Using genome-wide CRISPR-Cas9 activation and knockout screens, we identified peptide-specific HLA-C∗07 combinations that can interact with the surface molecules CD55 and heparan sulfate. These interactions closely resemble the HLA class-I interaction with the TCR regarding both the affinity range and the specificity of the peptide and HLA allele. These findings indicate that various proteins can specifically bind HLA class-I peptide complexes due to their polymorphic nature, which suggests there are more interactions like the ones we describe here.
