In mice, selleckchem adoptively transferred HBV-specific T cells trigger the recruitment of neutrophils and mononuclear cells that result in liver damage [9]. Notably, depletion of neutrophils prior to T cell transfer abolished the inflammatory infiltrate without hindering the antiviral efficiency of HBV-specific T cells or reducing CXCL-9 and CXCL-10 production, two chemokines induced by IFN-�� known to recruit inflammatory cells to the liver [10], [11]. The ability of virus-specific T cells to orchestrate such inflammatory phenomenon is generally ill defined in different human pathologies. Thus, the goal of the present study was to characterize the inflammatory potential of virus-specific T cells, analyzing their ability to produce different effector molecules in a non-cytopathic human infection such as HBV.

Since the role of interferon inducible chemokines have already been investigated [12] we focused our attention on IL-17 and CXCL-8 due to their inflammatory potential and ability to recruit neutrophils, which represents a key step in animal models of acute viral hepatitis. CXCL-8, which is the primary chemotactic factor for neutrophils, is a less well characterized T cell derived chemokine but can be produced in large quantities by T cells [13], [14] and elevated levels of CXCL-8 are found in patients with chronic liver disease [15] and chronic HBV patients prior to hepatic flares [16]. Likewise, IL-17 is known to recruit neutrophils [17] and has been associated with inflammatory diseases [18], [19], including hepatic flares in chronic HBV patients [20].

Since T cells display a degree of functional plasticity, the environment where T cells are activated can have a dramatic effect on their ultimate function [21], [22]. Thus, we hypothesized that the inflammatory cytokine milieu present during HBV infection can license T cells with the ability to produce CXCL-8 or IL-17. IL-15 is elevated in the liver of patients with active hepatitis [23], [24], has been demonstrated to induce IL-17 production [25], [26] and can stimulate CXCL-8 and MCP-1 expression from monocytes [27]. In addition, IL-7 can be up-regulated in the liver by inflammation and enhances T cell cytotoxic activity and cytokine production [28]. Therefore, we focused on these two cytokines, which are present in the liver during inflammation, and are known to impact T cell function.

Our data demonstrate that HBV-specific T cells produce CXCL-8, but not IL-17, during periods of liver inflammation and that this functional phenotype could be induced in greater than 90% of the detectable virus-specific T cell population Entinostat in acute/resolved HBV patients by exposure to IL-7 and IL-15. We characterized the phenotype and functional profile of CXCL-8+ T cells and demonstrated that this functional profile could be induced in unrelated CMV-specific T cells from healthy individuals.