Abstract
When associated with different receptors, the signalling adaptor DAP12 has been shown to both potentiate and attenuate the activation of leukocytes. But how can a protein with a single signalling motif elicit qualitatively different cellular responses? We describe a model of DAP12 function, whereby the quality of the cellular response (activation or inhibition) is modulated by the avidity of the interaction between the DAP12-associated receptor and its ligand. This model extends from previous studies of inhibitory signalling mediated by other adaptors, such as the Fc-receptor γ-chain and CD3ζ, and provides a potential mechanism for the conflicting phenotypes observed in studies of DAP12-deficient mice.
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References
Olcese, L. et al. Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells. J. Immunol. 158, 5083–5086 (1997).
Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).
Smith, K. M., Wu, J., Bakker, A. B., Phillips, J. H. & Lanier, L. L. Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161, 7–10 (1998).
Bouchon, A., Dietrich, J. & Colonna, M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).
Daws, M. R., Lanier, L. L., Seaman, W. E. & Ryan, J. C. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur. J. Immunol. 31, 783–791 (2001).
Chung, D. H., Seaman, W. E. & Daws, M. R. Characterization of TREM-3, an activating receptor on mouse macrophages: definition of a family of single Ig domain receptors on mouse chromosome 17. Eur. J. Immunol. 32, 59–66 (2002).
Bouchon, A., Hernandez-Munain, C., Cella, M. & Colonna, M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111–1122 (2001).
Bouchon, A., Facchetti, F., Weigand, M. A. & Colonna, M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410, 1103–1107 (2001).
Hamerman, J. A., Tchao, N. K., Lowell, C. A. & Lanier, L. L. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature Immunol. 6, 579–586 (2005).
Hamerman, J. A. et al. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177, 2051–2055 (2006).
Turnbull, I. R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).
Blasius, A. et al. A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-a. Blood 103, 4201–4206 (2004).
Fuchs, A., Cella, M., Kondo, T. & Colonna, M. Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44. Blood 106, 2076–2082 (2005).
Feng, J., Call, M. E. & Wucherpfennig, K. W. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. PLoS Biol. 4, e142 (2006).
Gosselin, P. et al. Induction of DAP12 phosphorylation, calcium mobilization, and cytokine secretion by Ly49H. J. Leukoc. Biol. 66, 165–171 (1999).
Makrigiannis, A. P. et al. Cloning and characterization of a novel activating Ly49 closely related to Ly49A. J. Immunol. 163, 4931–4938 (1999).
Lanier, L. L., Corliss, B., Wu, J. & Phillips, J. H. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693–701 (1998).
Jiang, K. et al. Syk regulation of phosphoinositide 3-kinase-dependent NK cell function. J. Immunol. 168, 3155–3164 (2002).
Chiesa, S. et al. Multiplicity and plasticity of natural killer cell signaling pathways. Blood 107, 2364–2372 (2006).
McVicar, D. W. & Burshtyn, D. N. Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Sci. STKE 2001, RE1 (2001).
Vivier, E., Nunes, J. A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).
McVicar, D. W. et al. DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J. Biol. Chem. 273, 32934–32942 (1998).
Levkowitz, G. et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4, 1029–1040 (1999).
Horne, W. C., Sanjay, A., Bruzzaniti, A. & Baron, R. The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol. Rev. 208, 106–125 (2005).
Vitale, M. et al. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J. Exp. Med. 187, 2065–2072 (1998).
Nakamura, M. C. et al. Mouse Ly-49D recognizes H-2Dd and activates natural killer cell cytotoxicity. J. Exp. Med. 189, 493–500 (1999).
Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).
Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002).
Tay, C. H. et al. The role of LY49 NK cell subsets in the regulation of murine cytomegalovirus infections. J. Immunol. 162, 718–726 (1999).
Sjolin, H. et al. Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection. J. Exp. Med. 195, 825–834 (2002).
Lee, S. H. et al. Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice. J. Exp. Med. 197, 515–526 (2003).
Bakker, A. B., Baker, E., Sutherland, G. R., Phillips, J. H. & Lanier, L. L. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc. Natl Acad. Sci. USA 96, 9792–9796 (1999).
Gibot, S. et al. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J. Exp. Med. 200, 1419–1426 (2004).
Turnbull, I. R. et al. DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J. Exp. Med. 202, 363–369 (2005).
Pasquier, B. et al. Identification of FcaRI as an inhibitory receptor that controls inflammation: dual role of FcRg ITAM. Immunity 22, 31–42 (2005).
Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nature Immunol. 4, 248–254 (2003).
Takahashi, K., Rochford, C. D. & Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647–657 (2005).
Cella, M. et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198, 645–651 (2003).
Paloneva, J. et al. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J. Exp. Med. 198, 669–675 (2003).
Sjolin, H. et al. DAP12 signaling regulates plasmacytoid dendritic cell homeostasis and down-modulates their function during viral infection. J. Immunol. 177, 2908–2916 (2006).
Blasius, A. L., Cella, M., Maldonado, J., Takai, T. & Colonna, M. Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood 107, 2474–2476 (2006).
Blasius, A. L. & Colonna, M. Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H. Trends Immunol. 27, 255–260 (2006).
Samelson, L. E. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu. Rev. Immunol. 20, 371–394 (2002).
Neel, B. G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).
Zhang, J., Somani, A. K. & Siminovitch, K. A. Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. Semin. Immunol. 12, 361–378 (2000).
Hardin, A. O., Meals, E. A., Yi, T., Knapp, K. M. & English, B. K. SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages. Biochem. Biophys. Res. Commun. 342, 547–555 (2006).
Fukao, T. & Koyasu, S. PI3K and negative regulation of TLR signaling. Trends Immunol. 24, 358–363 (2003).
Fukao, T. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nature Immunol. 3, 875–881 (2002).
Guha, M. & Mackman, N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J. Biol. Chem. 277, 32124–32132 (2002).
Kim, A. H., Khursigara, G., Sun, X., Franke, T. F. & Chao, M. V. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell. Biol. 21, 893–901 (2001).
Gratton, J. P. et al. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J. Biol. Chem. 276, 30359–30365 (2001).
Kagan, J. C. & Medzhitov, R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943–955 (2006).
Honda, K. et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).
Bave, U. et al. FcgRIIa is expressed on natural IFN-a-producing cells (plasmacytoid dendritic cells) and is required for the IFN-a production induced by apoptotic cells combined with lupus IgG. J. Immunol. 171, 3296–3302 (2003).
Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).
Vollmer, J. et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202, 1575–1585 (2005).
Savarese, E. et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107, 3229–3234 (2006).
Silverstein, R. D-galactosamine lethality model: scope and limitations. J. Endotoxin Res. 10, 147–162 (2004).
Remick, D. G., Newcomb, D. E., Bolgos, G. L. & Call, D. R. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13, 110–116 (2000).
Daws, M. R. et al. Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171, 594–599 (2003).
Makrigiannis, A. P. et al. Class I MHC-binding characteristics of the 129/J Ly49 repertoire. J. Immunol. 166, 5034–5043 (2001).
Gilfillan, S., Ho, E. L., Cella, M., Yokoyama, W. M. & Colonna, M. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nature Immunol. 3, 1150–1155 (2002).
Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nature Immunol. 3, 1142–1149 (2002).
Dietrich, J., Cella, M., Seiffert, M., Buhring, H. J. & Colonna, M. Cutting edge: signal-regulatory protein b1 is a DAP12-associated activating receptor expressed in myeloid cells. J. Immunol. 164, 9–12 (2000).
Tomasello, E. et al. Association of signal-regulatory proteins b with KARAP/DAP-12. Eur. J. Immunol. 30, 2147–2156 (2000).
Kumagai, H. et al. Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells. Biochem. Biophys. Res. Commun. 307, 719–729 (2003).
Aguilar, H. et al. Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J. Immunol. 173, 6703–6711 (2004).
Wright, G. J. et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J. Immunol. 171, 3034–3046 (2003).
Mousseau, D. D., Banville, D., L'Abbe, D., Bouchard, P. & Shen, S. H. PILRa, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRb. J. Biol. Chem. 275, 4467–4474 (2000).
Angata, T., Hayakawa, T., Yamanaka, M., Varki, A. & Nakamura, M. Discovery of Siglec-14, a novel sialic acid receptor undergoing concerted evolution with Siglec-5 in primates. FASEB J. 20, 1964–1973 (2006).
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Marco Colonna has stock options in the company Bioxell, Milan, Italy.
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Turnbull, I., Colonna, M. Activating and inhibitory functions of DAP12. Nat Rev Immunol 7, 155–161 (2007). https://doi.org/10.1038/nri2014
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DOI: https://doi.org/10.1038/nri2014
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