TAPBPR promotes editing of the HLA-B*44 peptide repertoire, increasing the presentation of peptides containing a C-terminal tryptophan

Aure Aflalo¹Arwen F Altenburg¹Marcel Wacker^2,3Jens Bauer^2,3,4Juliane Sarah Walz^2,3,4,5Louise Helen Boyle^1*

• ¹Department of Pathology, University of Cambridge, Cambridge, United Kingdom
• ²Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
• ³Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
• ⁴German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and University Hospital Tübingen, Tübingen, Germany
• ⁵Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany

Major histocompatibility complex class I (MHC-I) molecules play a key part in the adaptive immune response by presenting antigens to CD8+ T cells. The high degree of polymorphism in MHC-I leads to significant variation in their dependence on components of the antigen processing and presentation pathway, such as the transporter associated with antigen processing (TAP) and tapasin, and their affinity for the peptide editor TAP-binding protein related (TAPBPR). Here, we investigated the influence of TAPBPR on the cell surface phenotype and peptide repertoire presented by two human leukocyte antigen (HLA) class I allotypes, HLA-B*44:02 and -B*44:05, which are known to differ drastically in their dependence on tapasin. TAPBPR bound weakly to both HLA-B*44:02 and -B*44:05. In contrast to tapasin depletion, loss of TAPBPR has a limited effect on cell surface expression of these two molecules. Analysis of the immunopeptidomes presented in the presence and absence of TAPBPR revealed that TAPBPR expression restricted the peptide repertoire presented on HLA-B*44:05, while it diversified the repertoire presented on HLA-B*44:02. Overall, TAPBPR improved the predicted affinity of the peptides displayed on both the HLA-B*44 molecules. Furthermore, TAPBPR enhanced the presentation of peptides containing a C-terminal tryptophan residue. Our results show that TAPBPR can significantly impact the peptide repertoire of MHC-I molecules to which it binds weakly. Furthermore, this represents the first study that points to a role for TAPBPR in selecting a specific peptide sequence on MHC class I molecules.