Investigation of HLA-E intracellular transport and antigen presentation

Thesis

Apart from its primary role in presenting signal peptides derived from major histocompatibility complex (MHC) class I molecules to natural killer (NK) cells, MHC-E can also present pathogen-derived peptides to CD8+ T cells to inhibit pathogenesis upon infection. Recent discoveries demonstrated the effectiveness of MHC-E-restricted CD8+ T cell responses in controlling simian immunodeficiency virus (SIV) infection within a vaccine model, which has generated considerable interest in this non-canonical immune pathway.

MHC-E is an appealing target for immunotherapies and vaccine design due to its low genetic diversity and resistance to downregulation in response to pathogen infections and cancers. However, to fully exploit the potential of the unconventional human MHC-E (HLA-E)-restricted CD8+ T cell responses for therapeutic purposes, a comprehensive understanding of the intricate pathways governing HLA-E transport and antigen presentation is necessary, which has remained unclear thus far.

In this thesis, I delineated the basic trafficking patterns of HLA-E and explored the underlying mechanisms. The retention in the endoplasmic reticulum (ER) and the fast surface internalisation are the two major characteristics of HLA-E trafficking, which are predominantly shaped by its cytoplasmic tail and peptide repertoire. The ER retention of HLA-E primarily arises from the scarcity of high-affinity peptides and is further intensified by the absence of a C-terminal ER export motif. The fast internalisation of HLA-E results from a lysine/tryptophan-based endocytic motif on its cytoplasmic tail, while the lack of optimal peptides further decreased the surface stability of HLA-E.

Collectively, these findings unveil unique transport patterns and intricate regulatory mechanisms governing HLA-E trafficking, which not only advances our understanding of how HLA-E accomplishes its immunological roles through precise transport regulation but also provides valuable insights for the future development of immunotherapies and vaccines targeting the atypical HLA-E-restricted CD8+ T cell responses.

Authors: He, W

• DOI: 10.5287/ora-pm16rpgoj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: non-classical MHC-I; HLA-E trafficking; MHC-I transport regulation; antigen presenntation
• Subjects: Immunology