title: Essential role for IL-27 receptor signaling in prevention of Th1-mediated immunopathology during malaria infection.
abstract: Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R-deficient (WSX-1(-/-)) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4(+) T cells---but not CD8(+) T cells---prevented liver pathology in infected WSX-1(-/-) mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4(+) T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1(-/-) mice, indicating that additional, IL-10-independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.
authors.affiliation: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Emily Gwyer
authors.initials: EG
authors.lastname: Findlay
authors.forename: Rachel
authors.initials: R
authors.lastname: Greig
authors.forename: Jason S
authors.initials: JS
authors.lastname: Stumhofer
authors.forename: Julius C R
authors.initials: JC
authors.lastname: Hafalla
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Christiaan J
authors.initials: CJ
authors.lastname: Saris
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000097:blood; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018655:Lymphocyte Count; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018512:Parasitemia / Q000097:blood / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018123:Receptors, Interleukin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D016753:Interleukin-10; D007371:Interferon-gamma