Essential role for IL-27 receptor signaling in prevention of Th1-mediated immunopathology during malaria infection.
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.
Findlay
Emily Gwyer
EG
Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Greig
Rachel
R
Stumhofer
Jason S
JS
Hafalla
Julius C R
JC
de Souza
J Brian
JB
Saris
Christiaan J
CJ
Hunter
Christopher A
CA
Riley
Eleanor M
EM
Couper
Kevin N
KN
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
D016207:Cytokines; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D016753:Interleukin-10; D007371:Interferon-gamma