Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C

The mechanism of hepatitis C virus (HCV) involvement in innate immune responses and immune modulation has not been well characterized. In the present work, we studied Toll-like receptor (TLR) 2 and TLR4, which were recently recognized as the important components of innate immunity, as well as CD4(+) CD25(+) CD127(low/-) regulatory T cells (Tregs), which actively suppress pathological and physiological immune response during HCV infection. The study involved 31 chronic hepatitis C patients and 20 healthy controls. TLR2 and TLR4 expression in peripheral blood monocytes and the number of Tregs were examined by flow cytometric analysis. Overexpression of TLR2 and TLR4 was found in chronic hepatitis C patients as compared with controls. Furthermore, increased cytokine production, including that of beta-interferon, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, was observed in peripheral blood mononuclear cells from chronic hepatitis C patients after challenge with TLR2 and TLR4 agonists. The number of Tregs was significantly higher in chronic hepatitis C patients and the increased Tregs were associated with HCV genotype 1b. In vitro studies demonstrated that circulating Tregs suppress T-cell responses in chronic hepatitis C patients. Significant correlations were found between the viral load and Treg number and between TLR2 and TLR4 level in chronic hepatitis C patients. Taken together with other published data, these results suggest that TLR2, TLR4, and Tregs correlate closely with chronic HCV infection.