Recent studies have shown that Th17 responses were significantly increased in patients with CHB. Correlation analysis also suggested that Th17 cells play an important role in inflammatory response and cell mediated liver injury of CHB patients [
17‐
20]. In this study, we extended these observations by finding that Th17 responses were even significantly higher in AHB patients than CHB patients. In contrast, Th17 responses were not different between asymptomatic HBV carriers and healthy donors. Taken together, these data provided substantial evidences that Th17 cells contribute to inflammatory responses and cell-mediated liver injuries in individuals with HBV infection. Accordingly, understanding the regulatory mechanism of Th17 responses in HBV infected individuals is of particular importance, considering it may provide novel strategies for the treatment of patients with hepatitis B.
In attempt to investigate the mechanism underlying the increased Th17 response in patients with CHB, we first looked at the cytokine milieu related to the Th17 differentiation and found that TGF-β, IL-6 and IL-1β were increased in plasma of HBV infected individuals, irrespective their clinical manifestation. Consistent with these findings,
in vitro experiments showed that PBMCs produced TGF-β, IL-1β, and IL-6 upon stimulation with HBcAg. However, correlation analysis indicated that only the concentration of plasma TGF-β, but not IL-6 nor IL-1β, significantly correlated with increased Th17 responses in HBV infected patients. Thus, unlike the inhibitory role TGF-β plays during the HCV-specific Th17 response [
27], TGF-β may facilitate the development of Th17 responses in HBV infected subjects. Nevertheless, because TGF-β is also involved in CD4
+ CD25
+ regulatory T cells (Treg) differentiation and our previous study have found that the concentration of plasma TGF-β in CHB patients also correlated with the frequency of Treg [
28], the exact role of TGF-β in regulating Th17 response as well as balancing between Th17 and Treg in HBV infected individuals remains to be elucidated.
Consistent with our previous finding in patients with tuberculosis, we found IL-6R expression on CD4
+ T cells, but not plasma IL-6, correlated with the Th17 response in HBV infected individuals [
29]. However, unlike
Mycobacterium tuberculosis antigens which down-regulated IL-6R expression on CD4
+
T cells from patients with tuberculosis, HBV antigen (HBcAg) up-regulated IL-6R expression on CD4
+ T cells from patients with CHB. More importantly, our
in vitro data validated that blockade of IL-6R signaling on CD4
+ T cells significantly inhibited antigen non-specific (PMA/Ionomycin-stimulated) and HBcAg antigen-specific IL-17, but not IFN-γ, production by CD4
+ T cells, which was not surprised considering the fact that no requirement of IL-6 for Th1 differentiation. Thus, while both infections modulate IL-6R expression on CD4
+ T cells, the effect of
Mycobacterium tuberculosis infection was markedly different from that of HBV infection. In addition, the difference was likely due to
in vivo "tuning" of CD4
+ T cells by chronic exposure to inflammatory environment superimposed by HBV infection (including circulating HBV antigens), since HBcAg, similar to
Mycobacterium tuberculosis antigens, down-regulated IL-6R expression on CD4
+ T cells in healthy donors. While further investigations are warranted to identify the exact mechanisms that account for "tuning" CD4
+ T cells
in vivo, circulating HBV antigens as well as the cytokines induced by HBV infection might be most potential candidates that are responsible for such different effect. For example, elevated TGF-β in patients with hepatitis B might "tune" CD4
+ T cells with increased sensitivity to IL-6R signaling through inhibition of SOCS3[
30,
31].