# Human Cytomegalovirus Antigen Presentation by HLA‐G in Infected Cells

## TL;DR

This study shows that HLA-G can present human cytomegalovirus peptides in infected cells, but these peptides do not trigger strong immune responses.

## Contribution

First evidence that HLA-G presents HCMV peptides, but not as a functional antigen-presenting mechanism.

## Key findings

- HLA-G presented 22 HCMV-derived peptides in infected cells.
- Peptides binding HLA-G did not stimulate CD8+ T cell cytokine production in short-term assays.
- Some peptides bound both HLA-G and HLA-E but were not recognized by NK cell receptors.

## Abstract

HLA‐E and ‐G class Ib molecules were considered unrelated to viral antigen presentation. HLA‐E binds nonamers from the leader sequences of other HLA‐I molecules and the human cytomegalovirus (HCMV) UL40 protein, interacting with CD94/NKG2 NK cell receptors. Yet, evidence that HLA‐E may present some pathogen‐derived peptides to CD8+ T lymphocytes has been reported. By contrast, HLA‐G binds a broad spectrum of endogenous sequences but its role in antigen presentation is unknown. An experimental approach was set up to search for HCMV antigens displayed by HLA‐G in infected cells. Among the analysed peptidome, 22 sequences corresponding to 16 HCMV molecules were identified; 17 peptides were confirmed to interact in vitro with HLA‐G of which 10 displayed characteristic anchor residues. As compared to the response in short‐term (6 h) assays to immunodominant IE‐1 and pp65 antigens, none of the HLA‐G‐binding peptides stimulated cytokine production by CD8+ T cells from HCMV‐seropositive blood donors (n = 15). Following a 14‐day peptide stimulation of PBMC and expansion with IL‐2, CD8+ T cells specifically responding to a subset of these viral antigens were detected in some individuals, yet were not restricted by HLA‐G in functional assays. A subset of viral peptides did bind to both HLA‐G and ‐E but were not recognised by CD94/NKG2 NK cell receptors. Our results provide the first evidence that HLA‐G may display potentially immunogenic viral peptides in HCMV‐infected cells, yet do not support their ability to promote HLA‐G‐restricted CD8+ T cell responses nor to modulate NK cell functions.