MHC class II-positive perivascular microglial cells mediate resistance to Cryptococcus neoformans brain infection.
Acquired resistance to the CNS pathogen Cryptococcus neoformans is mediated by CD4(+) T lymphocytes primed by exposure to antigen in the context of major histocompatibility class II (MHC II) molecules. In mouse brain, parenchymal and perivascular microglial cells may express interferon-gamma (IFN-gamma)-inducible MHC class II marker and thus interact with CD4(+) T cells. Primed effector T cells are retained in the infected CNS if antigen is encountered in proper MHC context and may deliver signals that potentiate microglia to enhanced fungistasis. Vaccinated C57BL6/J mice resist an ordinarily lethal C. neoformans rechallenge, but identically treated congenic Abeta(o/o) mice (MHC class II-deficient; CD4(+) T-cell-deficient) do not. Nor can Abeta(o/o) mice be adoptively immunized by infusion of lymphocytes from vaccinated C57BL6/J donors, as are severe combined immunodeficient (SCID) mice (MHC class II-intact, lymphocyte-deficient). Chimeric (C57BL/6J:Abeta(o/o)) mice with class II expression likely on perivascular microglia only were, like SCID mice, capable of adoptive immunization against C. neoformans brain infection. To the contrary, chimeric mice with class II expression likely only on parenchymal microglia were not capable of effective adoptive immunization against C. neoformans brain infection. Therefore, in order to mediate resistance to infection, primed CD4(+) T cells must interact with the replenishable perivascular microglial subset that lies in close proximity to cerebral vasculature. Although T cells may supply help in the form of inflammatory cytokines to parenchymal microglia, expression of class II on these cells appears unnecessary for antifungal activity.
Biology Department, Clarkson University, Potsdam, New York 13699, USA. kmaguirr@clarkson.edu
Karen
K
Aguirre
Shannon
S
Miller
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001808:Blood Vessels / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D001921:Brain / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002450:Cell Communication / Q000276:immunology; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000472:pathogenicity; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007114:Immunization / Q000379:methods; D016919:Meningitis, Cryptococcal / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology
D000949:Histocompatibility Antigens Class II