The glycosphingolipid repertoire affects HLA class I function. (October 2022)

• Record Type: Journal Article
• Authors: Jongsma, Marlieke; de Waard, Antonius; Cabukusta, Birol; Wuhrer, Manfred; Zhang, Tao; Brummelkamp, Thijn; Neefjes, Jacques; Spaapen, Robbert
• Is Part Of: Molecular immunology. Volume 150(2022)
• Page Start: 3
• Publication Date: 2022-10
• Subjects: Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2022.05.020
• Languages: English
• ISSNs: 0161-5890

Abstract

Abstract : HLA class I (HLA-I) molecules drive immune responses by presenting antigen-derived peptides to T-lymphocytes. Loading of these peptides into the HLA-I binding groove occurs via a multistep process which can be hijacked by viruses and tumors for immune escape. Using iterative genome-wide haploid genetic screening we identified the protease SPPL3 to enhance HLA-I antigen presentation by inhibiting B3GNT5 activity, an enzyme of the glycosphingolipid (GSL) synthesis pathway. GSL profiling by LCMS demonstrated SPPL3-deficient cells to express high levels of sialic acid containing B3GNT5-synthesized GSLs compared to wild type cells. These GSLs localize in close proximity to HLA-I molecules -as revealed by LCMS analysis of the local membrane surrounding HLA-I-thereby shielding membrane proximal HLA-I epitopes from epitope specific antibody recognition. On a functional level, HLA-I shielding also resulted in loss of ligand (LIR-1) binding and a defect in CD8+ T cells activation. HLA-I shielding GSLs are overexpressed on several subtypes of cancer, suggesting a novel form of immune escape. Moreover, pharmacological inhibition of these GSLs on AML cells abolished HLA-I shielding. Our findings demonstrate that the composition of the GSL repertoire determines the efficacy of antigen presentation and represents a potential treatment target in infection and cancer.