STING was initially described as a sensor of intracellular bacterial and viral DNA and a promising adjuvant target in innate immune cells; more recently STING has also been shown to detect endogenous DNA and play a role in tumor immunity and autoimmune disease development. Thus far STING has been studied in macrophages and dendritic cells. Here, we provide the first evidence of STING activation in T cells, in which STING agonists not only provoke IFN-I production and ISG expression, mirroring the response of innate cells, but are also capable of activating cell stress and death pathways. Our results suggest a reevaluation of STING agonist-based therapies may be necessary to identify possible effects on the T cell compartment. Conversely, the effects of STING on T cells could potentially be harnessed for therapeutic applications.
This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.
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 CD4 T helper 17 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 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 ability of antigen presenting cells to produce IL-23 and IL-1â 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 nematodes can also dampen pathogenic Th17 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.
CBA mice infected with the helminthSchistosomamansonidevelop severe CD4 T cell-mediated hepaticgranulomatous 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 (Tg) 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 Tg T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 stimulated by syngeneic IL-12p40-deficient DCs. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficientor IL-1R antagonist treated CBA mice developed markedly reduced hepatic immunopathologywith a dampened egg Ag-specific IL-17 response. These results demonstrate the IL-23-IL-1-IL-17 axis to play a central role in the development of severe schistosome egg-induced immunopathology.
In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs is uneven and strain dependent. CBA mice develop severe hepatic granulomatous inflammation associated with prominent T helper 17 (Th17) cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. Such Th17 cells fail to develop in low-pathology BL/6 mice, and the reasons for these strain-specific differences in antigen (Ag) presenting cell (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 (CLR) CD209a, a murine homologue of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), than 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 over-expression 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.
No abstract
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.
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.
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