Abstract
Compared with the ubiquitous expression of type I (IFNα and IFNβ) interferon receptors, type III (IFNλ) interferon receptors are mainly expressed in epithelial cells of mucosal barriers of the of the intestine and respiratory tract. Consequently, IFNλs are important for innate pathogen defense in the lung and intestine. IFNλs also determine the outcome of hepatitis C virus (HCV) infections, with IFNλ4 inhibiting spontaneous clearance of HCV. Because viral clearance is dependent on T cells, we explored if IFNλs can directly bind to and regulate human T cells. We found that human B cells and CD8+ T cells express the IFNλ receptor and respond to IFNλs, including IFNλ4. IFNλs were not inhibitors but weak stimulators of B- and T-cell responses. Furthermore, IFNλ4 showed neither synergistic nor antagonistic effects in co-stimulatory experiments with IFNλ1 or IFNα. Multidimensional flow cytometry of cells from liver biopsies of hepatitis patients from IFNλ4-producers showed accumulation of activated CD8+ T cells with a central memory-like phenotype. In contrast, CD8+ T cells with a senescent/exhausted phenotype were more abundant in IFNλ4-non-producers. It remains to be elucidated how IFNλ4 promotes CD8 T-cell responses and inhibits the host immunity to HCV infections.
Highlights
Hepatitis C virus (HCV) is a parenteral transmitted hepatotropic virus that chronically infects an estimated 71 million persons worldwide (WHO, 2017)
Longer incubation times or higher doses of IFNλ1 did not increase the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation (Fig 1B), suggesting that the overall lower response to IFNλ1 could be due to differential IFNλ receptor (IFNλR) expression patterns within individual PBMC populations
We determined the responsiveness to IFNλ1 of distinct cell subsets isolated from PBMCs, including total CD3+ T cells, or sorted CD4+ or CD8+ T cells, sorted CD19+ B cells, CD14+ monocytes, and CD3−/CD16+ NK cells
Summary
Hepatitis C virus (HCV) is a parenteral transmitted hepatotropic virus that chronically infects an estimated 71 million persons worldwide (WHO, 2017). Chronic hepatitis C (CHC) leads to some degree of liver fibrosis and in 15–25% cirrhosis develops after 10–40 yr (Lauer & Walker, 2001). Depletion of CD8+ T cells before experimental infection of previously protected chimpanzees led to HCV persistence until CD8+ T-cell response recovered and an HCV-specific CD8+ T-cell response emerged (Shoukry et al, 2003). Depletion of CD4+ cells in previously protected chimpanzees led to HCV persistence and the emergence of CD8+ escape variants (Grakoui et al, 2003). These findings suggested that CD4+ T cells promote persistence of protective immunity, whereas virus-specific CD8+ T cells primarily function as the key effectors
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