Mobilization of γδ T Cells and IL-10 Production at the Acute Phase of Hepatitis E Virus Infection in Cytomegalovirus Carriers

Alterations in the gamma delta T cell compartment have been reported in immunocompromised individuals infected with hepatitis E virus (HEV)-g3. We now report the analysis of blood gamma delta T cells from acutely HEV-infected individuals in the absence of immunosuppression. In these patients, non-V delta 2 (ND2) gamma delta T cells outnumbered otherwise predominant V delta 2 cells selectively in human CMV (HCMV)-seropositive patients and were higher than in HCMVpos controls, mimicking HCMV reactivation, whereas their serum was PCR-negative for HCMV. Stimulation of their lymphocytes with HEY-infected hepatocarcinoma cells led to an HEV-specific response in gamma delta subsets of HCMVpos individuals. HEV infection was associated with a lowered expression of TIGIT, LAG-3, and CD160 immune checkpoint markers on ND2 effector memory cells in HCMVneg but not in HCMVpos HEV patients. gamma delta cell lines, predominantly ND2, were generated from patients after coculture with hepatocarcinoma cells permissive to HEV and IL-2/12/18. Upon restimulation with HEV-infected or uninfected cells and selected cytokines, these cell lines produced IFN-gamma and IL-10, the latter being induced by IL-12 in IFN-gamma-producing cells and upregulated by HEV and IL-18. They were also capable of suppressing the proliferation of CD3/CD28-activated CD4 cells in transwell experiments. Importantly, IL-10 was detected in the plasma of 10 of 10 HCMVpos HEV patients but rarely in controls or (HCMVHEV)-H-ne-H-g patients, implying that gamma delta cells are probably involved in IL-10 production at the acute phase of infection. Our data indicate that HEV mobilizes a pool of ND2 memory cells in HCMV carriers, promoting the development of an immunoregulatory environment.

Automated summary

Alterations in the gamma delta T cell compartment have been reported in individuals infected with hepatitis E virus (HEV)-g3, with a specific increase in ND2 cells in HCMV-positive patients. HEV-specific responses were observed in gamma delta subsets of HCMV-positive individuals, suggesting an involvement of gamma delta cells in IL-10 production during acute phase infection.