The lower incidence of allergy and autoimmune diseases in developing countries has been associated with a high prevalence of parasitic infections. Here we provide direct experimental evidence that parasites can exert bystander immunosuppression of pathogenic T cells that mediate autoimmune diseases. Infection of mice with Fasciola hepatica resulted in recruitment of dendritic cells, macrophages, eosinophils, neutrophils, and CD4+ T cells into the peritoneal cavity. The dendritic cells and macrophages in infected mice expressed IL-10 and latency-associated peptide, and they had low surface expression of costimulatory molecules and/or MHC class II. Furthermore, most CD4+ T cells in the peritoneal cavity of infected mice secreted IL-10, but not IFN-γ or IL-4. There was a less significant expansion of CD4+Foxp3+ T cells. F. hepatica-specific Tr1-type clones generated from infected mice suppressed proliferation and IFN-γ production by Th1 cells. Infection was associated with suppression of parasite-specific Th1 and Th2 responses, which was reversed in IL-10-defective mice. Infection with F. hepatica also exerted bystander suppression of immune responses to autoantigens and attenuated the clinical signs of experimental autoimmune encephalomyelitis. Protection was associated with suppression of autoantigen-specific IFN-γ and IL-17 production. The suppression of Th1 and Th17 responses and attenuation of experimental autoimmune encephalomyelitis by F. hepatica was maintained in IL-10−/− mice but was reversed by neutralization of TGF-β in vivo. Our study provides evidence that F. hepatica-induced IL-10 subverts parasite-specific Th1 and Th2 responses, but that F. hepatica-induced TGF-β plays a critical role in bystander suppression of autoantigen-specific Th1 and Th17 responses that mediate autoimmune diseases.

The factors that determine persistence or clearance of hepatitis C virus (HCV) infection are poorly understood. The CD4 T cell responses to the HCV core protein were examined in a cohort of women infected with a single genotype of HCV. CD4 T cells from HCV-infected patients secreted interferon (IFN)-gamma in response to peptides from 4 immunodominant regions of the core protein, and these responses were stronger in persistently infected women. Interleukin (IL)-10 was also produced by CD4 T cells from HCV-infected subjects in response to the same core peptides. Furthermore, HCV core-specific CD4 T cell clones secreted either IFN-gamma or IL-10 but not IL-4. These findings demonstrate that T helper type 1 and regulatory T cells are induced against the same epitopes on the core protein during HCV infection.

It is well documented that long term potentiation (LTP) is impaired in the hippocampus of the aged animal. Among the changes that contribute to this impairment is an increase in hippocampal concentration of the pro-inflammatory cytokine interleukin-1␤ (IL-1␤), and increased IL-1␤-induced signaling. In this study we investigated the possibility that these changes were a consequence of decreased concentration of the anti-inflammatory cytokine, IL-4, and decreased IL-4-stimulated signaling. We report that functional IL-4 receptors are expressed on granule cells of the dentate gyrus and that receptor activation results in phosphorylation of JAK1 and STAT6. Hippocampal IL-4 concentration was decreased with age, and this was accompanied by a decrease in phosphorylation of JAK1 and STAT6. The evidence indicates that IL-4 modulates expression of IL-1␤ mRNA and protein and that it attenuates IL-1␤-induced impairment of LTP and phosphorylation of JNK and c-Jun. We argued that, if a decrease in hippocampal IL-4 concentration significantly contributed to the age-related impairment in LTP, then restoration of IL-4 should restore LTP. To test this, we treated rats with VP015 (phospholipid microparticles-incorporating phosphatidylserine), which increases IL-4 concentration in hippocampus. The data indicate that the VP015-induced increase in IL-4 concentration in hippocampus of aged rats and lipopolysaccharide (LPS)-treated rats was accompanied by a reversal of the age-related and LPSinduced impairment in LTP in perforant path granule cell synapses. We propose that interplay between proinflammatory and anti-inflammatory responses impact significantly on synaptic function in the hippocampus of the aged rat.Inflammatory changes contribute to the deficits that accompany several neurodegenerative conditions, and, in animal models, it has been repeatedly shown that inflammation is associated with deficits in synaptic function and consequently impairments in cognitive function. For example, peripheral administration of lipopolysaccharide (LPS 1 ), which increases pro-inflammatory cytokine interleukin-1␤ (IL-1␤) concentration in the brain, is accompanied by evidence of cell stress and neuronal cell death (1, 2) as well as impairment of hippocampaldependent learning and memory (3). Deficits in long term potentiation (LTP) have been reported in aged rats (4) and in other experimental conditions in which hippocampal IL-1␤ concentration is increased (5-9). Significantly, administration of anti-inflammatory agents restores synaptic function in LPStreated animals in which IL-1␤ concentration is enhanced (6, 10, 11).Inflammatory responses are regulated in part by anti-inflammatory cytokines, including IL-4 and IL-10, which are produced by T cells and cells of the innate immune system. T helper type 2 (Th2) cells secrete IL-4, IL-5, and IL-10 and are responsible for reciprocally regulating the T helper type 1 (Th1) subtype, which mediate cellular and inflammatory responses. IL-4 also plays a role in promoting the differentiation of naïve T ce...

Immune responses induced with helminth parasites have been extensively studied, but there is limited information on those to Fasciola hepatica, especially on the subtype of T cell induced with this parasite. We investigated the local and systemic T cell responses of different strains of mice following oral infection with doses of metacercariae from F. hepatica. Spleen cells from BALB/c and 129Sv/Ev mice given a low-dose (5 metacercariae) infection exhibited a Th2 response, producing high levels of the cytokines IL-4 and IL-5, and low levels of IFN-gamma and IL-2. In contrast, C57BL/6 mice showed a mixed Th1/Th2 response. A more marked polarization to a Th2 response was observed in BALB/c, 129Sv/Ev exposed to a high-dose (15 metacercariae) infection and the C57BL/6 mice also exhibited a clear Th2 response. IL-4 defective (IL-4-/-) C57BL/6 mice infected with 5 metacercariae produced less IFN-gamma and more IL-5 compared to their wild-type C57BL/6 counterparts, suggesting that IL-4 is important in establishing the Th2 type response in murine fasciolosis. However, the secretion of IFN-gamma and IL-2 was completely suppressed in the high-dose infection and this was also observed in IL-4-/- mice. Thus, liver flukes may secrete molecules that downregulate Th1 responses. T cell responses in the mesenteric (MLN) and hepatic lymph nodes (HLN) were also examined since newly excysted juveniles infect through the intestinal wall of their host before migrating to the hepatic tissue. Cells from both MLN and HLN secreted higher levels of IL-4 and IL-5 compared to spleen cells. We also observed a difference in cytokine profiles secreted by the MLN and HLN, which may reflect responses to antigens liberated by newly excysted juveniles and hepatic stage parasites, respectively.

The majority of hepatitis C virus (HCV) infections become chronic, despite the presence of HCV-specific cellular and humoral immune responses. We have previously suggested that IL-10-secreting antigen-specific regulatory T cells may contribute to viral persistence, and demonstrate here that peripheral blood mononuclear cells (PBMC) from chronically HCVinfected patients secrete IL-10, but not IFN-+ , in response to HCV nonstructural protein 4 (NS4). A neutralizing anti-IL-10 antibody restored this defective antigen-specific IFN-+ production in vitro. Furthermore, PBMC from normal individuals secreted IL-10 in response to NS4, suggesting that cells of the innate immune system, in addition to T cells, produced IL-10 in the HCV-infected patients. Cell separation experiments revealed that the innate IL-10 was produced by blood monocytes, but not dendritic cells (DC). In addition, NS4 inhibited IL-12 production by PBMC in response to LPS and IFN-+ , and Th1 responses to recall antigens in normal individuals. Furthermore, supernatants from NS4-stimulated monocytes inhibited LPS-induced maturation of DC and suppressed their capacity to stimulate proliferation and IFN-+ production by allospecific T cells. Our data suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells.