title: Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection.
abstract: Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-kappaB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology.
authors.affiliation: Infectious Diseases Division, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.forename: Tony
authors.initials: T
authors.lastname: Yang
authors.forename: Kapilan
authors.initials: K
authors.lastname: Kugathasan
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takenaka
authors.forename: Gordon
authors.initials: G
authors.lastname: Gaschler
authors.forename: Ali
authors.initials: A
authors.lastname: Ashkar
authors.forename: Martin
authors.initials: M
authors.lastname: Stampfli
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramson
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Earl
authors.initials: E
authors.lastname: Brown
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D000098815:T-bet Transcription Factor