The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.
Immunity
; 54(1): 132-150.e9, 2021 01 12.
Article
in English
| MEDLINE | ID: covidwho-957143
ABSTRACT
HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Glycosphingolipids
/
Histocompatibility Antigens Class I
/
Aspartic Acid Endopeptidases
/
Glycosyltransferases
/
CD8-Positive T-Lymphocytes
/
Glioma
/
HLA Antigens
/
Immunotherapy
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Immunity
Journal subject:
Allergy and Immunology
Year:
2021
Document Type:
Article
Affiliation country:
J.immuni.2020.11.003
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