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Interest in MHC-E-restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian immunodeficiency virus (SIV) infection in a vaccine model. The development of vaccines and immunotherapies utilizing human MHC-E (HLA-E)-restricted CD8+ T cell response requires an understanding of the pathway(s) of HLA-E transport and antigen presentation, which have not been clearly defined previously. We show here that, unlike classical HLA class I, which rapidly exits the endoplasmic reticulum (ER) after synthesis, HLA-E is largely retained because of a limited supply of high-affinity peptides, with further fine-tuning by its cytoplasmic tail. Once at the cell surface, HLA-E is unstable and is rapidly internalized. The cytoplasmic tail plays a crucial role in facilitating HLA-E internalization, which results in its enrichment in late and recycling endosomes. Our data reveal distinctive transport patterns and delicate regulatory mechanisms of HLA-E, which help to explain its unusual immunological functions.

Original publication

DOI

10.1084/jem.20221941

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

08/2023

Volume

220

Addresses

Nuffield Department of Medicine, Center for Immuno-Oncology, University of Oxford, Oxford, UK.

Keywords

CD8-Positive T-Lymphocytes, Animals, Humans, Vaccines, Histocompatibility Antigens Class I, Antigen Presentation, HLA-E Antigens