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Sci. STKE, 31 January 2006
Vol. 2006, Issue 320, p. re1
[DOI: 10.1126/stke.3202006re1]


Inhibition of Immune Responses by ITAM-Bearing Receptors

Jessica A. Hamerman and Lewis L. Lanier*

Department of Microbiology and Immunology and the Cancer Research Institute, University of California at San Francisco, 513 Parnassus Avenue, Box 0414, HSE1001, San Francisco, CA 94143–0414, USA.

Gloss: Cells of the immune system have many cell surface receptors that are composed of more than one transmembrane-anchored protein—one or more proteins binds the extracellular ligand and distinct proteins, named signaling adaptors, transmit a signal into the cell. These signaling adaptors have intracellular amino acid sequences designated immunoreceptor tyrosine-based activation motifs (ITAMs) containing tyrosine residues that are phosphorylated after the receptor binds ligand. These multisubunit receptors can transmit potent signals for cellular activation through ITAM phosphorylation and the recruitment of tyrosine kinases of the Syk and ZAP-70 family. More recently, it has been appreciated that some members of the multisubunit immune receptor family can also transmit signals that inhibit cellular activation. The focus of this Review, with four figures and 48 citations, is on the evidence for and mechanism of inhibition by ITAM-containing multisubunit receptors. This article would be useful in teaching or learning about regulatory mechanisms involved in controlling immune responses.

*Corresponding author. E-mail, lewis.lanier{at}

Citation: J. A. Hamerman, L. L. Lanier, Inhibition of Immune Responses by ITAM-Bearing Receptors. Sci. STKE 2006, re1 (2006).

The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3.
Y.-C. Lin, D.-Y. Huang, C.-L. Chu, Y.-L. Lin, and W.-W. Lin (2013)
Science Signaling 6, ra71
   Abstract »    Full Text »    PDF »
Plasmacytoid Dendritic Cells, Interferon Signaling, and Fc{gamma}R Contribute to Pathogenesis and Therapeutic Response in Childhood Immune Thrombocytopenia.
K. Sehgal, X. Guo, S. Koduru, A. Shah, A. Lin, X. Yan, and K. M. Dhodapkar (2013)
Science Translational Medicine 5, 193ra89
   Abstract »    Full Text »    PDF »
Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity.
L. C. Ndhlovu, S. Lopez-Verges, J. D. Barbour, R. B. Jones, A. R. Jha, B. R. Long, E. C. Schoeffler, T. Fujita, D. F. Nixon, and L. L. Lanier (2012)
Blood 119, 3734-3743
   Abstract »    Full Text »    PDF »
ITAM-Coupled Receptors Inhibit IFNAR Signaling and Alter Macrophage Responses to TLR4 and Listeria monocytogenes.
L. Huynh, L. Wang, C. Shi, K.-H. Park-Min, and L. B. Ivashkiv (2012)
J. Immunol. 188, 3447-3457
   Abstract »    Full Text »    PDF »
IgG1 and IVIg induce inhibitory ITAM signaling through Fc{gamma}RIII controlling inflammatory responses.
M. Aloulou, S. Ben Mkaddem, M. Biarnes-Pelicot, T. Boussetta, H. Souchet, E. Rossato, M. Benhamou, B. Crestani, Z. Zhu, U. Blank, et al. (2012)
Blood 119, 3084-3096
   Abstract »    Full Text »    PDF »
The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses.
T. Nakano-Yokomizo, S. Tahara-Hanaoka, C. Nakahashi-Oda, T. Nabekura, N. K. Tchao, M. Kadosaki, N. Totsuka, N. Kurita, K. Nakamagoe, A. Tamaoka, et al. (2011)
J. Exp. Med. 208, 1661-1671
   Abstract »    Full Text »    PDF »
Inhibitory ITAM Signaling Traps Activating Receptors with the Phosphatase SHP-1 to Form Polarized "Inhibisome" Clusters.
S. Pfirsch-Maisonnas, M. Aloulou, T. Xu, J. Claver, Y. Kanamaru, M. Tiwari, P. Launay, R. C. Monteiro, and U. Blank (2011)
Science Signaling 4, ra24
   Abstract »    Full Text »    PDF »
ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling.
D. B. Graham, H. M. Akilesh, G. B. Gmyrek, L. Piccio, S. Gilfillan, J. Sim, R. Belizaire, J. A. Carrero, Y. Wang, G. S. Blaufuss, et al. (2010)
Blood 116, 3208-3218
   Abstract »    Full Text »    PDF »
DAP12 Is Required for Macrophage Recruitment to the Lung in Response to Cigarette Smoke and Chemotaxis toward CCL2.
L. L. Koth, C. J. Cambier, A. Ellwanger, M. Solon, L. Hou, L. L. Lanier, C. L. Abram, J. A. Hamerman, and P. G. Woodruff (2010)
J. Immunol. 184, 6522-6528
   Abstract »    Full Text »    PDF »
TREM2- and DAP12-Dependent Activation of PI3K Requires DAP10 and Is Inhibited by SHIP1.
Q. Peng, S. Malhotra, J. A. Torchia, W. G. Kerr, K. M. Coggeshall, and M. B. Humphrey (2010)
Science Signaling 3, ra38
   Abstract »    Full Text »    PDF »
Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II.
B. Liang, C. Workman, J. Lee, C. Chew, B. M. Dale, L. Colonna, M. Flores, N. Li, E. Schweighoffer, S. Greenberg, et al. (2008)
J. Immunol. 180, 5916-5926
   Abstract »    Full Text »    PDF »
Innate Immune Responses to TREM-1 Activation: Overlap, Divergence, and Positive and Negative Cross-Talk with Bacterial Lipopolysaccharide.
K. Dower, D. K. Ellis, K. Saraf, S. A. Jelinsky, and L.-L. Lin (2008)
J. Immunol. 180, 3520-3534
   Abstract »    Full Text »    PDF »
Inhibitory ITAM Signaling by Fc{alpha}RI-FcR{gamma} Chain Controls Multiple Activating Responses and Prevents Renal Inflammation.
Y. Kanamaru, S. Pfirsch, M. Aloulou, F. Vrtovsnik, M. Essig, C. Loirat, G. Deschenes, C. Guerin-Marchand, U. Blank, and R. C. Monteiro (2008)
J. Immunol. 180, 2669-2678
   Abstract »    Full Text »    PDF »
Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation.
X. Hu, J. Chen, L. Wang, and L. B. Ivashkiv (2007)
J. Leukoc. Biol. 82, 237-243
   Abstract »    Full Text »    PDF »
IgA Fc receptor I signals apoptosis through the FcR{gamma} ITAM and affects tumor growth.
Y. Kanamaru, H. Tamouza, S. Pfirsch, D. El Mehdi, C. Guerin-Marchand, M. Pretolani, U. Blank, and R. C. Monteiro (2007)
Blood 109, 203-211
   Abstract »    Full Text »    PDF »
Diminished Production of Monocyte Proinflammatory Cytokines during Human Immunodeficiency Virus Viremia Is Mediated by Type I Interferons.
J. C. Tilton, A. J. Johnson, M. R. Luskin, M. M. Manion, J. Yang, J. W. Adelsberger, R. A. Lempicki, C. W. Hallahan, M. McLaughlin, J. M. Mican, et al. (2006)
J. Virol. 80, 11486-11497
   Abstract »    Full Text »    PDF »
DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection.
H. Sjolin, S. H. Robbins, G. Bessou, A. Hidmark, E. Tomasello, M. Johansson, H. Hall, F. Charifi, G. B. K. Hedestam, C. A. Biron, et al. (2006)
J. Immunol. 177, 2908-2916
   Abstract »    Full Text »    PDF »

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