Interleukin-10 and Viral Clearance: Translation to Viral Hepatitis

Abstract

Brooks DG, Trifilo MK, Edelmann KH, Teyton L, McGavern DB, Oldstone MB (Viral Immunology Laboratory, Molecular and Integrative Neuroscience Department, Scripps Research Institute, La Jolla, California). Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006;12:1301–1309. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG. (Immune Regulation Laboratory, La Jolla Institute for Allergy and Immunology, La Jolla, California). Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 2006;203:2461–2472. The groups of Michael Oldstone and Matthias von Herrath recently described the important role of interleukin (IL)-10 in determining viral clearance and persistence by using the lymphocytic choriomeningitis virus (LCMV) mouse model (Nat Med 2006;12:1301–1309; J Exp Med 2006;203:2461–2472). The LCMV mouse system is the main model system of chronic high-load viral infection in which inoculation of adult mice with specific strains and or doses can lead to acute resolving or sustained viremia (J Virol 2004;78:5535–5545). For example, adult mice infected with LCMV Armstrong rapidly clear the virus and establish a stable memory T-cell pool, whereas infection with a naturally selected isolate of LCMV Armstrong, called clone 13, results in prolonged, persisting infection. With increasing time and in the presence of high virus load, the T cells gradually lose their ability to exert antiviral effector functions in response to viral antigen, a phenomenon called T-cell exhaustion (Nat Immunol 2005;6:873–879). By studying the immune response to these 2 LCMV strains, Brooks et al and Ejraenes et al observed that IL-10 was significantly increased in LCMV clone 13-infected mice with persistent infection (Nat Med 2006;12:1301–1309; J Exp Med 2006;203:2461–2472). Significantly more IL-10 was detected by an RNA protection assay performed on total splenic RNA and in the supernatants of cultured splenocytes from LCMV clone 13-infected mice compared with Armstrong-infected mice. Nevertheless, it remains unclear where the majority of IL-10 originates in vivo (dendritic cells, T cells, or other?), because both studies come to a different conclusion on the origin of IL-10. Brooks et al suggest that dendritic cells are directly responsible for the most substantial increase in IL-10 production during persistent infection (Nat Med 2006;12:1301–1309). However, Ejrnaes et al (J Exp Med 2006;203:2461–2472) favor IL-10 production by CD4+ T cells, skewed toward IL-10 production by dendritic cell subsets. Whatever the source might be, both studies clearly show that IL-10 leads to impaired T-cell responses. Indeed, CD8+ T cells from LCMV clone 13-infected mice secreted interferon (IFN)-γ only during the early phase of infection and it was almost completely lost at later time points when high levels of IL-10 were produced. In contrast, IFN-γ production by CD8+ T cells from LCMV Armstrong-infected mice peaked later and was sustained. The in vivo blockade of the IL-10 receptor with a neutralizing antibody resulted in a rapid resolution of the persistent infection with LCMV clone 13 that coincided with a restoration of the IFN-γ production of virus-specific CD8+ T cells (J Exp Med 2006;203:2461–2472). Similarly, the genetic removal of IL-10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses (Nat Med 2006;12:1301–1309). Thus, both studies clearly show that the inhibition of IL-10 signaling in vivo leads to the enhancement of antiviral CD8+ T-cell function resulting in viral clearance in a mouse model of LCMV infection. This indicates that a single molecule that is up-regulated during viral infection may directly induce viral persistence by down-tuning the virus-specific T-cell response. The success or failure of the virus-specific CD8+ T-cell response was not determined by the high initial viral load per se, indicating that even an overwhelming viral infection can be rapidly controlled when an antiviral immune response is maintained. In addition, the initial high level of virus did also not affect the number or quality of memory precursors and T cells in IL-10–deficient mice because these memory cells were able to prevent reinfection upon viral challenge (Nat Med 2006;12:1301–1309). Thus, by avoiding T-cell exhaustion and viral persistence, it is possible to develop a population of functionally active virus-specific memory T cells. Brooks et al and Ejrnaes et al also studied programmed death 1 (PD-1) expression on virus-specific CD8+ T cells (Nat Med 2006;12:1301–1309; J Exp Med 2006;203:2461–2472). PD-1 has recently been described as another key signaling pathway elucidated using the same LCMV model system. Indeed, Barber et al (Nature 2006;439:682–687) showed that PD-1 is highly expressed by dysfunctional CD8+ T cells during chronic LCMV infection. They also showed that when antibodies were used to block the PD-1–PD-L1 pathway in vivo during chronic infection, virus-specific CD8+ T cells were potently enhanced. Brooks et al observed a lack of PD-1 expression by CD8+ T cells on day 9 in clone-13 infected IL-10–deficient mice (Nat Med 2006;12:1301–1309) and suggest that this may be due to the rapid control of viral replication in the absence of IL-10. Ejrnaes et al found a 3-fold reduction of PD-1 expression on T cells from anti–IL-10R–treated mice compared with IgG1 isotype antibody treated mice on day 90, indicating that anti–IL-10R treatment may lead to a decrease in PD-1 expression on T cells and thus contribute to abrogation of T-cell exhaustion (J Exp Med 2006;203:2461–2472). These studies about the role of IL-10 in determining viral clearance and persistence have important implications for hepatitis B virus (HBV) and hepatitis C virus (HCV) immunobiology and therapy. Indeed, virus-specific CD8+ T-cell responses play an important role in the outcome and pathogenesis of several viral infections, including HBV and HCV (Nat Immunol 2005;6:873–879; Nature 2005;436:946–952; Nat Rev Immunol 2005;5:215–229; J Virol 2005;79:9369–9380). For example, the central role of CD8+ T-cell–mediated immunity in HBV and HCV infection has been suggested by the temporal association of the onset of functional virus-specific CD8+ T-cell responses and the first phase of viral control (J Exp Med 2000;191:1499–1512; Gastroenterology 1999;117:1386–1396; J Exp Med 2001;194:1395–1406). In addition, depletion studies of CD8+ T cells in HBV- and HCV-infected chimpanzees have clearly demonstrated that CD8+ cells are the key effector cells; viral clearance correlated precisely with the recovery of virus-specific CD8+ T cells (J Exp Med 2003;197:1645–1655; J Virol 2003;77:68–76). However, in both HBV and HCV infection, the virus-specific immune response is sometimes unable to control viral replication, thereby allowing the virus to persist. The mechanisms responsible for the failure of the virus-specific CD8+ T-cell response are not completely understood. Next to the emergence of viral escape mutations, physical deletion of virus-specific T cells and loss of T-cell function have been suggested to be central mechanisms of T-cell failure in viral hepatitis (Nat Rev Immunol 2005;5:215–229; J Virol 2005;79:9369–9380; Antiviral Res 2006;69:129–141). Indeed, several groups have described dysfunctional virus-specific CD8+ T cells in the blood and liver of chronically HBV- and HCV-infected patients. However, the mechanisms responsible for the loss of T-cell function are currently unknown. Lack of CD4+ T-cell help, action of regulatory T cells, inadequate CD8+ T-cell differentiation or the genetic restriction have been discussed as possible reasons for the dysfunction (Nat Rev Immunol 2005;5:215–229; J Virol 2005;79:9369–9380; Antiviral Res 2006;69:129–141; Nat Med 2002;8:379–385; J Virol 2007;81:945–953). So, what are the lessons learned from these elegant mouse studies for human viral hepatitis? Importantly, they provide a potential explanation for the T-cell dysfunction typically observed in chronic viral hepatitis that may lead to the development of new immunotherapeutic strategies. Noteworthy, elevated levels of IL-10 have been shown to be associated with persistent HCV infection (World J Gastroenterol 2002;8:562–566) and intrahepatic IL-10–producing CD4+ T cells have been described in chronic infection (Hepatology 2004;40:125–132). In addition, intrahepatic CD8+ T cells from chronically HCV infected patients have been shown to suppress in vitro proliferative responses of liver-derived lymphocytes in an HCV-specific and IL-10–dependent manner (J Clin Invest 2004;113:963–972). One study also showed that in vitro neutralization of IL-10 activity in peripheral blood mononuclear cells from HCV-infected patients led to the recovery of activity in nonresponsive T cells (Clin Immunol 2005;117:57–64). In summary, these combined results suggest that IL-10 is elevated and biologically active in persistent HCV infection and may thus be responsible for the T-cell dysfunctions typically observed in the setting of chronic infection. Importantly, HCV-specific CD8+ T cells have also been recently shown to display a high expression of PD-1 in the peripheral blood and liver of chronically HCV-infected patients (J Virol 2006;81:2545–2553). In addition, in vitro blockade of PD-1 (J Virol 2006;81:2545–2553) and IL-10 (Clin Immunol 2005;117:57–64) leads to a better proliferation of HCV-specific CD4+ and/or CD8+ T cells. Thus, the modulation of IL-10 or PD-1 signaling in persistent human viral infection may be a future therapeutic strategy leading to enhanced control or elimination of persistent viral infection. For example, an early neutralization of IL-10 activity after HCV exposure, occurring, for example, during needle stick accidents or the inhibition of IL-10 and PD-1 or both during chronic HBV and HCV infections may be feasible therapeutic approaches. Clearly, a better understanding of the mechanisms of T-cell failure during viral infection and their translation to clinical virology and immunology will be an important and exciting area in the near future.