Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis

Finger, Eduardo; Brodeur, Peter H.; Hernández, Héctor J.; Stadecker, Miguel J.

doi:10.1002/eji.200526344

Cited by 7 publications

(8 citation statements)

References 72 publications

(82 reference statements)

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“…The discovery of an expanded and remarkably restricted CD4 T cell response against the major Sm-p40 egg Ag in schistosome-infected highpathology CBA mice (7) enabled us to develop a mouse transgenicallyexpressing a Vα11.3Vβ8 TCR specific for the immunodominant peptide Sm-p40 234–246 . Indeed, 96% of splenic CD4 T cells from Tg mice expressed Vβ8 compared to only 9% in T cells from WT controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the described proinflammatorycytokine milieu, we have found that high pathology in schistosome-infected CBA mice correlates with a significant expansion of CD4 T cells recognizing the immunodominantepitope234–246 of the major Sm-p40 schistosome egg antigen (Sm-p40 234–246 ) (7). Sm-p40 is one of the most abundant components of the schistosome egg and was found to elicit a strong Th1 polarized response in CBA (H-2 k ) mice (2, 8).…”

Section: Introductionmentioning

confidence: 99%

“…Sm-p40 is one of the most abundant components of the schistosome egg and was found to elicit a strong Th1 polarized response in CBA (H-2 k ) mice (2, 8). Analysis of the I-A k -restricted Sm-p40 234–246 -specific CD4 T cells revealed a clonally restricted population with a TCR expressing Vα11.3Vβ8(7), which paved the way for the development of a novel CBA mouse expressing atransgenic (Tg) TCR specific for Sm-p40 234–246 .…”

Section: Introductionmentioning

confidence: 99%

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The Pathogenic Th17 Cell Response to Major Schistosome Egg Antigen Is Sequentially Dependent on IL-23 and IL-1β

Shainheit

Lasocki

Finger

et al. 2011

The Journal of Immunology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Pathogenic Th17 Cell Response to Major Schistosome Egg Antigen Is Sequentially Dependent on IL-23 and IL-1β

Shainheit

Lasocki

Finger

et al. 2011

The Journal of Immunology

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“…This locus corresponds to a region on human chromosome 5, 20 Mb from the D5S410 marker, which was used to identify the Sm1 locus that controls intensity of infection in humans (24). Another likely linkage is to MHC genes located near this region, as they have been suggested to play a role in human and murine schistosome infection (19 –22, 36). …”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis

Shainheit

Bazzone²,

Rutitzky³

et al. 2009

The Journal of Immunology

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Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F2 progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F2 mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-γ, and TNF-α by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-γ production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.

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“…To date, the glycosylation status of Sm-p40 has not been determined, and it is conceivable that it may not be glycosylated (C. H. Hokke, personal communication). In the CBA and C3H mice a vast proportion of the anti-Sm-p40 T cell repertoire is directed against immunodominant epitope peptide Sm-p40 234–246 [32], utilizing a T cell receptor (TCR) composed of Vá11.3Vâ8 [33]. This striking immunodominance prompted the development of CBA mice expressing a transgenic (Tg) TCR specific for Sm-p40 234–246 [31] (Box 1).…”

Section: Parasites and Parasite Antigensmentioning

confidence: 99%

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

et al. 2012

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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.

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Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis

Cited by 7 publications

References 72 publications

The Pathogenic Th17 Cell Response to Major Schistosome Egg Antigen Is Sequentially Dependent on IL-23 and IL-1β

The Pathogenic Th17 Cell Response to Major Schistosome Egg Antigen Is Sequentially Dependent on IL-23 and IL-1β

Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

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