title: CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10.
abstract: The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis.
authors.affiliation: Centre for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: Catriona T
authors.initials: CT
authors.lastname: Prendergast
authors.affiliation: Centre for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Sanin
authors.affiliation: Centre for Immunology and Infection, Department of Biology, University of York, York, United Kingdom.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Cook
authors.affiliation: Centre for Immunology and Infection, Department of Biology, University of York, York, United Kingdom adrian.mountford@york.ac.uk.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Mountford
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000494:pharmacology; D007814:Larva / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D012550:Schistosoma mansoni / Q000276:immunology*; D012552:Schistosomiasis / Q000276:immunology* / Q000469:parasitology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10