Human herpesvirus-6-specific interleukin 10-producing CD4⁺ T cells suppress the CD4⁺ T-cell response in infected individuals

Human herpesvirus-6 (HHV-6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV-6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4⁺ T cells and PBMCs but not CD8 ⁺ T cells from HHV-6-infected individuals was stimulated with HHV-6-infected cell lysates. Moreover, HHV-6-stimulated CD4⁺ T cells from HHV-6-infected individuals have suppressive activity on naive CD4 ⁺ T and CD8⁺ T cells from HHV-6-uninfected individuals. However, no increased proportion of CD4⁺ CD25⁺ Treg cells from HHV-6-infected individuals contributed to the suppressive activity of the HHV-6-stimulated CD4⁺ T cells from HHV-6-infected individuals. Transwell experiments, ELISA and anti-IL-10 antibody blocking experiment demonstrated that IL-10 may be the suppressive cytokine required for suppressive activity of CD4⁺ T cells from HHV-6-infected individuals. Results of intracellular interleukin (IL)-10 and IL-4 further implicated the HHV-6-specific IL-10-producing CD4⁺ T cells in the suppressive activity of CD4⁺ T cells from HHV-6-infected individuals. Results of intracellular interferon (IFN)-γ demonstrated a decreased frequency of HHV-6-specific IFN-γ-producing CD4⁺ T, but not CD8⁺ T cells in HHV-6-infected individuals, indicating that it was the CD4 ⁺ Th1 responses in HHV-6-infected individuals that were selectively impaired. Our findings indicated that HHV-6-specific IL-10-producing CD4 ⁺ T cells from HHV-6-infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL-10 production, with a few cells expressing IFN-γ, but none expressing IL-4. These cells may play an important role in latent HHV-6 infection.