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* Infectious Diseases Division, Centre for Gene Therapeutics, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;
Department of Experimental Immunology, Tohoku University, Sendai, Japan;
Department of Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; and
Howard Hughes Medical Institute and Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by funds from the Canadian Institutes for Health Research and the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Zhou Xing, Room 4012-MDCL, Department of Pathology and Molecular Medicine and Division of Infectious Diseases, Center for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada. E-mail address: xingz{at}mcmaster.ca
3 Abbreviations used in this paper: DAP12, DNAX-activating protein of 12 kDa; TREM, triggering receptor expressed on myeloid cell; MCMV, murine CMV; SIRP
, signal regulatory protein ; WT, wild type; BCG, bacillus Calmette-Guérin; MDL-1, myeloid DAP12-associated protein 1; NP, nuclear protein; i.d., intradermal(ly); ICCS, intracellular cytokine staining; Ad, adenovirus; BAL, bronchoalveolar lavage; PGN, peptidoglycan; IKK, IB kinase ; M.tb, Mycobacterium tuberculosis; CF, culture filtrate protein.
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