Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection

Maziar Divangahi, Tony Yang, Kapilan Kugathasan, Sarah McCormick, Shunsuke Takenaka, Gordon Gaschler, Ali Ashkar, Martin Stampfli, Jack Gauldie, Jonathan Bramson, Toshiyuki Takai, Earl Brown, Wayne M. Yokoyama, Naoko Aoki, Zhou Xing

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32 Scopus citations

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-κB 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.

Original languageEnglish
Pages (from-to)4015-4026
Number of pages12
JournalJournal of Immunology
Volume179
Issue number6
DOIs
StatePublished - Sep 15 2007

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    Divangahi, M., Yang, T., Kugathasan, K., McCormick, S., Takenaka, S., Gaschler, G., Ashkar, A., Stampfli, M., Gauldie, J., Bramson, J., Takai, T., Brown, E., Yokoyama, W. M., Aoki, N., & Xing, Z. (2007). Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection. Journal of Immunology, 179(6), 4015-4026. https://doi.org/10.4049/jimmunol.179.6.4015