# Exacerbation of Anti‐Cytomegalovirus Immunity and Mobilization of γ9δ1 T Cells During the Acute Phase of Hepatitis E Virus Infection

## TL;DR

This study finds that Hepatitis E Virus (HEV) infection may reactivate anti-Cytomegalovirus (CMV) immunity and mobilize specific T cells, particularly γ9δ1 T cells.

## Contribution

The study identifies a novel link between HEV infection and the activation of γ9δ1 T cells in response to CMV.

## Key findings

- γ9δ1 T cells are selectively mobilized in HEV patients.
- CMV-seropositive HEV patients show exacerbated anti-CMV immune responses.
- γ9δ1 T cells can be activated by CMV, but not by HEV.

## Abstract

HEV causes chronic infections that are detrimental to immunocompromised patients. Previous studies showed alterations of γδ T cell subsets at the acute phase of HEV infection. To assess a possible role of CMV, we have examined the frequencies and responses to CMV and HEV of blood γδ T cell subsets from control donors and acute‐phase HEV patients with or without CMV. CMV DNA was mostly undetectable in the blood of CMV‐seropositive HEV patients, and anti‐CMV antibodies were only slightly elevated. However, Vγ9negVδ1pos cells were enriched in vivo, suggesting an increased CMV burden. In contrast, γ9δ1 cells were depleted in most HEV patients, regardless of CMV status. Culturing with IL‐2 and IL‐15 led to strong γ9δ1 T cell enrichment in samples from HEV patients. After IL‐2/IL‐15 sensitization, analysis of IFN‐γ responses to CMV‐infected fibroblasts or hepatocarcinoma cells (with IL‐18) showed innate responsiveness to CMV in γ9δ1, γ9δ2, and γ9negδ1pos cells in some control subjects and CMV‐seronegative patients. However, these responses were selectively exacerbated in CMV‐seropositive HEV patients, who also showed significant αβ T cell responses to CMV. This indicates reactivation of anti‐CMV immunity. Responses to HEV‐infected HepG2 cells remained undetected. IFN‐γ responses were not associated with TCR downmodulation in γ9δ2 or γ9negδ1pos cells. However, IFN‐γ‐producing γ9δ1 from HEV patients were characterized by high TCR expression, which was downmodulated after stimulation with CMV‐infected fibroblasts or CMV/HEV‐coinfected HepG2 cells. We conclude that γ9δ1 T cells are selectively mobilized in HEV patients and can be activated by CMV.