title: IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria.
abstract: Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA for Irgm1 and Irgm3 was found in the brains and spleens of infected mice at times of peak IFN-γ production. Irgm3-/- but not Irgm1-/- mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+ T cells within the brain. Although antigen-specific proliferation of transferred CD8+ T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred into Irgm3-/- recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens of Irgm3-/- mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology in Irgm3-/- mice occurs due to impaired generation of CD8+ effector function. This defect is nonintrinsic to CD8+ T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.
authors: Molecular Immunopathology Unit, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors: Jintao
authors: J
authors: Guo
authors: Molecular Immunopathology Unit, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors: James A
authors: JA
authors: McQuillan
authors: Molecular Immunopathology Unit, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors: Belinda
authors: B
authors: Yau
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors: Gregory S
authors: GS
authors: Tullo
authors: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors: Carole A
authors: CA
authors: Long
authors: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.
authors: Patrick
authors: P
authors: Bertolino
authors: Immune Imaging Group, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.
authors: Ben
authors: B
authors: Roediger
authors: Immune Imaging Group, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia.
authors: Wolfgang
authors: W
authors: Weninger
authors: Departments of Medicine, Molecular Genetics and Microbiology, and Immunology, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, USA Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, North Carolina, USA.
authors: Gregory A
authors: GA
authors: Taylor
authors: Molecular Immunopathology Unit, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors: Nicholas H
authors: NH
authors: Hunt
authors: Molecular Immunopathology Unit, Sydney Medical School, University of Sydney, New South Wales, Australia.
authors: Helen J
authors: HJ
authors: Ball
authors: Immune Imaging Group, Centenary Institute for Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia a.mitchell@centenary.org.au.
authors: Andrew J
authors: http://orcid.org/0000-0003-4454-853X
authors: AJ
authors: Mitchell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054405:Chemokine CCL3 / Q000096:biosynthesis; D054407:Chemokine CCL4 / Q000096:biosynthesis; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis; D007371:Interferon-gamma / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C096000:Ifi1 protein, mouse; D007370:Interferon Type I; D015850:Interleukin-6; D012333:RNA, Messenger; D007371:Interferon-gamma; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C101131:Igtp protein, mouse
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