title: Pulmonary M. tuberculosis infection delays Th1 immunity via immunoadaptor DAP12-regulated IRAK-M and IL-10 expression in antigen-presenting cells.
abstract: Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung.
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Jeyanathan
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: McCormick
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Lai
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Afkhami
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: C R
authors.initials: CR
authors.lastname: Shaler
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: C N
authors.initials: CN
authors.lastname: Horvath
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Damjanovic
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Zganiacz
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Barra
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Ashkar
authors.affiliation: McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Jordana
authors.affiliation: McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Aoki
authors.affiliation: 1] McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada [2] Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Xing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C484963:Tyrobp protein, mouse; D016753:Interleukin-10; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse