Hepatitis C virus core protein triggers expansion and activation of CD4⁺CD25⁺ regulatory T cells in chronic hepatitis C patients

Abstract

CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Tregs) are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus (HCV)-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein (HCVc) directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 87 treatment-naïve chronic HCV-infected patients, CD4⁺CD25⁺ Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. CD4⁺, CD8⁺, CD4⁺CD25⁺ and CD4⁺CD25⁻ T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor (TLR) ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4⁺CD25⁺ Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4⁺CD25⁺ Treg proliferation, but inhibited CD4⁺CD25⁻ T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand (poly I:C) and the TLR4 ligand (lipopolysaccharide, LPS), the TLR2 ligand (lipoteichoic acid, LTA) and HCVc both inhibited TCR-induced CD4⁺ T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4⁺CD25⁺ Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.