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In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3–grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1β and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell–mediated severe immunopathology in helminthic disease.

Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to IL-17-producing CD4 T helper (Th17) cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a solely Th2-polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6. The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the production of IL-23 and IL-1β by antigen presenting cells following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with intestinal nematodes can also dampen pathogenic Th17 cell responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.

The cytoplasmic protein Stimulator of Interferon Genes (STING) plays an essential role in sensing cytoplasmic DNA of intracellular pathogens and initiating IFN type I responses in myeloid cells. It can also directly bind cyclic dinucleotides produced by intracellular bacteria or by the DNA-binding cyclic GMP-AMP (cGAMP) synthase. To date, the signaling mechanisms involving STING activation has been studied in macrophages and dendritic cells. Taking into consideration the fact that STING is highly expressed in the thymus and spleen, we decided to investigate its functional role in T cells. We revealed that STING can be activated in T cells by DMXAA (5,6-dimethylxanthenone-4-acetic acid), which binds to the same site in murine STING as cGAMP and triggers phosphorylation of TBK1 and IRF3 resulting in IFNβ production and increased expression of interferon stimulated genes. In contrast to T lymphocytes obtained from C57B6 WT mice, STING−/− T cells displayed no phosphorylation of TBK1/IRF3, and produced no detectable IFNβ upon stimulation. DMXAA treatment also resulted in IFNgamma secretion by WT cells, while DMXAA-treated knockouts produced only a small amount of IFNgamma comparable to unstimulated WT T cells. Both CD4+ and CD8+ subsets of WT T cells responded to DMXAA with phosphorylation of TBK1/IRF3 and IFNβ production, but only CD4+ cells produced IFNgamma. By performing RNA sequencing, numerous differences in gene expression (including interferon stimulated genes) between WT and STING−/− T cells before and after DMXAA stimulation were identified. The work was supported by the Russian Science Foundation (grant no. 115-15-00100 ).

Background. Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues. Methods. We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium- endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni-infected highpathology CBA mice and low-pathology C57BL/6 mice. Results. S. haematobium-infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood. Conclusions. This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40–deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40–deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23–IL-1–IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.

The cytoplasmic protein Stimulator of Interferon Genes (STING) plays an essential role in sensing intracellular pathogens and initiating type I IFN responses in myeloid cells. STING detects the presence of cytoplasmic DNA presented by various DNA-binding proteins (e.g. IFI16, DDX41, DAI, RNA Pol III); it also directly binds cyclic dinucleotides produced by intracellular bacteria or by the DNA-binding cyclic GAMP synthase (c-GAS). Once activated, STING phosphorylates TBK1 and IRF3 to trigger type I IFN production. To date STING has only been studied in macrophages and dendritic cells, but early reports showed expression of STING in a variety of tissues including the thymus and spleen, prompting us to ask whether STING might have a functional role in T cells, which account for the majority of cells in the thymus and a larger proportion of cells in the spleen than macrophages and dendritic cells. Here, we show that STING can be activated in T cells by the small molecule DMXAA, resulting in IFNβ production and increased expression of numerous interferon stimulated genes (ISG)—the first evidence to our knowledge of type I IFN production by T cells. Furthermore, RNA-sequencing data revealed unanticipated differences between unstimulated wild type and STING-/- T cells, with STING -/- T cells exhibiting increased expression of genes associated with cytotoxic T lymphocytes, indicating that STING-mediated signaling in T cells may regulate the development of particular T cell subsets.

The magnitude of immunopathology and pro-inflammatory cytokine production in murine Schistosoma mansoni infection is strain-dependent. Severe hepatic egg-induced granulomatous inflammation in CBA mice is associated with Th1 and Th17 cytokine responses, whereas BL/6 mice develop milder lesions in a Th2-polarized cytokine environment. Pathogenic Th17 cell responses in CBA mice are dependent on the production of IL-1β and IL-23 by egg-stimulated dendritic cells (DC); by comparison, such Th17 cells fail to develop in BL/6 mice. The reasons for strain-dependent differences in DC reactivity to eggs remain unclear. Genome-wide gene profiling revealed significant differences between CBA vs. BL/6 DCs in C-type lectin receptors (CLRs), a family of pattern recognition receptors that binds glycans such as those produced by schistosome eggs. Expression of the CLR CD209a, a murine homologue of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), was strikingly higher in several APC populations from CBA mice; however, only CBA DC, but not macrophages, B cells, or granulocytes elicited Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DC, and over-expression in BL/6 DC, demonstrated CD209a to be necessary for egg-induced DC production of ERK1/2 map kinase-dependent IL-1β and IL-23 as well as subsequent Th17 cell development. These findings reveal a novel mechanism controlling the development of Th17 cell-mediated immunopathology in helminthic disease.

Schistosomiasis is a CD4 T cell-mediated inflammatory disease caused by parasitic helminths of the genus schistosoma. The main cause of morbidity and mortality in both humans and an experimental mouse model are tissue-lodged parasite eggs. For reasons not yet fully understood, the severity of immunopathology varies widely amongst mouse strains: CBA/J develop severe disease with an elevated Th17 response whereas C57BL/6 develop mild pathology with a Th2-polarized response. In view of several studies showing that Programmed Death-1 and its ligands PD-L1 and PD-L2 suppress a variety of T cell-mediated immune responses, we hypothesized that this co-inhibitory pathway downregulates the granulomatous response to schistosome eggs, thus preventing severe pathology. We now show that infection in BL/6 mice results in a larger population of PD-L2+ CD11c(hi) splenocytes than in CBA mice. Moreover, PD-L2 deficient BL/6 mice display markedly exacerbated hepatic granulomatous inflammation together with a significant increase in Th17 cells, whereas in PD-L1 deficient BL/6 mice these parameters are not significantly different from WT controls. These results suggest that the induction of PD-L2 expression represents a powerful means to control excessive T cell-mediated immunopathology in this major parasitic disease.

In murine schistosomiasis, immunopathology and cytokine production in response to schistosome eggs is uneven and strain dependent. Infected CBA mice develop severe hepatic egg-induced granulomatous inflammation associated with prominent Th17 and Th1 cytokine responses, whereas in BL/6 mice milder lesions develop in a Th2-dominant cytokine environment. The pathogenic Th17 response in CBA mice is largely dependent on IL-1β and IL-23 produced by schistosome egg-stimulated dendritic cells (DC); by comparison, this pro-inflammatory cytokine pathway fails to materialize in low-pathology BL/6 mice. Whereas requirements for Th17 cell differentiation elicited by CBA DC are apparent, the reason for such a strain difference in APC reactivity to live eggs is not known. Initial gene profiling disclosed a significant difference in C-type lectin receptor (CLR) expression between CBA and BL/6 bone marrow derived DC. CLR are pattern recognition receptors capable of binding carbohydrates, including those secreted by schistosome eggs. A significant increase in CLR expression, particularly murine homologues of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), was documented by real-time PCR and flow cytometry on tissues from infected CBA mice, including liver, spleen and granuloma cells. Current work is aimed at elucidating the functional implications of differential CLR expression on T cell subset differentiation, activation and pathogenicity during the schistosome infection.

Infection with parasitic helminths of the genus Schistosoma results in a wide range of immunopathology. Studies in murine schistosomiasis suggest that Th17 cells play a major role in the development of severe pathology; conversely, regulatory T (Treg) cells represent a mechanism to curtail excessive inflammation. We assessed by flow cytometry the profile of peripheral blood (PB) CD4 T cells in a cohort of children with urinary schistosomiasis from the village of Pakh, Department of Richard Toll, Senegal. S. hematobium-infected children with bladder pathology had a significantly higher percentage of PB IL-17+ cells with higher RORγt+/ Foxp3+ and IL-17+/ IL-10+ cell ratios than infected children without pathology. To investigate the relationship between PB values and target organs, we also examined the PB T cell response in murine S. mansoni infection (S. hematobium is non-permissive in mice) and, similar to humans, found a significantly higher percentage of CD4+ IL-17+ cells in high-pathology CBA mice than in low-pathology BL/6 mice. Moreover, a significant increase in IL-17+ cells in spleen and liver granulomas together with lower Foxp3+ cells in the spleen of CBA mice denoted a good correlation between PB and target organs. Our findings for the first time demonstrate an association between pathology and PB Th17 cells in human schistosomiasis and suggest human PB T cell subsets to faithfully reflect those mediating lesions in organs affected by the disease.