Our studies in this report implicate that circulating ��-catenin signaling CD4+ T cells from HCV-infected individuals are skewed toward Th2 and Th17 cell differentiation via secretion of TSLP from HCV-infected hepatocytes (Fig. 1). In addition, a combination of TSLP with HCV proteins (i.e., NS3/5) increases Th17 differentiation (Fig. 6). Interestingly, another group showed that TGF-β and IL-10, which are induced by the HCV NS4 protein, suppress Th1 and Th17 responses in HCV-infected patients.23 Given that the above study used the NS4 protein alone, it is possible that this viral protein alone is able to dampen the immune response by way of production of IL-10,

which, in turn counteracts Th17 responses. However, our study is based on the whole virus, JFH-1, containing all HCV proteins and thereby DCs in exposure to JFH-1 HCV virus produce TSLP. Moreover, the production of TSLP depends on TGF-β and has been shown to antagonize IL-10 production. Recent studies have reported that HCV-specific IL-17-producing CD8+ T cells are detectable in blood and liver of chronically HCV-infected patients.8, 24 In addition, IL-17-producing CD4+ T cells have also been shown to be present in chronic HCV-infected patients.22, 23, 25 These results suggest that HCV-specific IL-17-producing T cells are

not limited to the CD4+ T cells alone, but also CD8+ T cells. Nevertheless, the molecular and cellular mechanisms underlying the generation of these Th17 cell buy PF-02341066 responses in HCV infection were not elucidated. Our results suggest a mechanistic link between TSLP derived from HCV-infected hepatocytes and the infiltration of IL-17-producing Th17 T-cells MCE公司 into the HCV-infected liver. HCV-derived proteins play a role in inducing TGF-β, IL-6, and IL-21 production from monocyte-differentiated DCs.26 In terms of a potential relationship between TSLP and these cytokines, there is no existing report for a direct effect of these cytokines in TSLP induction. However, it is worthwhile to point that

IL-6 is well known to activate STAT3 and TSLP is also able to induce STAT3 activation.27 Thus, there is the convergence of intracellular pathways downstream of TSLP and IL-6 and thereby these cytokines act in similar ways leading to skew T-cell responses towards Th17 cells. Our studies in this report demonstrate that HCV infection of hepatocytes induce TSLP production by these cells, resulting in the activation and maturation of DCs with increased expression of CCL17, CCL22, and CCL20 chemokines. Importantly, the blockade of TSLP action by neutralizing antibodies prevents DC activation/maturation conditioned by HCV-infected hepatocytes (Fig. 4). Thus, there may be at least two different pathways for triggering DC activation and maturation during viral infection: (1) direct sensing of viral PAMP by DCs, and (2) crosstalk between virus-infected cells and DCs.