Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 311 (5769): 1927-1932

Copyright © 2006 by the American Association for the Advancement of Science

A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation

Nobutaka Suzuki,1 Shinobu Suzuki,1* Douglas G. Millar,2{dagger} Midori Unno,1 Hiromitsu Hara,1 Thomas Calzascia,2 Sho Yamasaki,1 Tadashi Yokosuka,1 Nien-Jung Chen,3 Alisha R. Elford,2 Jun-ichiro Suzuki,4{ddagger} Arata Takeuchi,1 Christine Mirtsos,3 Denis Bouchard,3 Pamela S. Ohashi,2 Wen-Chen Yeh,3§|| Takashi Saito1||

Abstract: IRAK-4 is a protein kinase that is pivotal in mediating signals for innate immune responses. Here, we report that IRAK-4 signaling is also essential for eliciting adaptive immune responses. Thus, in the absence of IRAK-4, in vivo T cell responses were significantly impaired. Upon T cell receptor stimulation, IRAK-4 is recruited to T cell lipid rafts, where it induces downstream signals, including protein kinase C{theta} activation through the association with Zap70. This signaling pathway was found to be required for optimal activation of nuclear factor {kappa}B. Our findings suggest that T cells use this critical regulator of innate immunity for the development of acquired immunity, suggesting that IRAK-4 may be involved in direct signal cross talk between the two systems.

1 Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
2 Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
3 Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
4 Department of Molecular Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.

* Present address: Nihon Schering K. K. Research Center, BMA 3F, 1-5-5, Minatojima-minami-machi, Chuo-ku, Kobe 650-0047, Japan.

{dagger} Present address: Faculty of Life Sciences, University of Manchester, C-2259 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.

{ddagger} Present address: Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishitokyo-shi, Tokyo 202-8585, Japan.

§ Present address: Amgen San Francisco, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

|| To whom correspondence should be addressed. E-mail: saito{at} (T.S.); wyeh{at} (W.-C.Y.)

Interleukin-1 Receptor-Associated Kinase 4 Is Essential for Initial Host Control of Brucella abortus Infection.
F. S. Oliveira, N. B. Carvalho, A. P. M. S. Brandao, M. T. R. Gomes, L. A. de Almeida, and S. C. Oliveira (2011)
Infect. Immun. 79, 4688-4695
   Abstract »    Full Text »    PDF »
Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell Types.
E. Y. Chiang, X. Yu, and J. L. Grogan (2011)
J. Immunol. 186, 1279-1288
   Abstract »    Full Text »    PDF »
IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease.
K. A. Staschke, S. Dong, J. Saha, J. Zhao, N. A. Brooks, D. L. Hepburn, J. Xia, M. F. Gulen, Z. Kang, C. Z. Altuntas, et al. (2009)
J. Immunol. 183, 568-577
   Abstract »    Full Text »    PDF »
Differential Regulation of Foxp3 and IL-17 Expression in CD4 T Helper Cells by IRAK-1.
U. Maitra, S. Davis, C. M. Reilly, and L. Li (2009)
J. Immunol. 182, 5763-5769
   Abstract »    Full Text »    PDF »
The Protein Kinase C-Responsive Inhibitory Domain of CARD11 Functions in NF-{kappa}B Activation To Regulate the Association of Multiple Signaling Cofactors That Differentially Depend on Bcl10 and MALT1 for Association.
R. R. McCully and J. L. Pomerantz (2008)
Mol. Cell. Biol. 28, 5668-5686
   Abstract »    Full Text »    PDF »
The Long Isoform of Cellular FLIP Is Essential for T Lymphocyte Proliferation through an NF-{kappa}B-Independent Pathway.
N. Zhang, K. Hopkins, and Y.-W. He (2008)
J. Immunol. 180, 5506-5511
   Abstract »    Full Text »    PDF »
The Tumor Suppressor Death-Associated Protein Kinase Targets to TCR-Stimulated NF-{kappa}B Activation.
Y.-T. Chuang, L.-W. Fang, M.-H. Lin-Feng, R.-H. Chen, and M.-Z. Lai (2008)
J. Immunol. 180, 3238-3249
   Abstract »    Full Text »    PDF »
The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease.
M. Fukata, K. Breglio, A. Chen, A. S. Vamadevan, T. Goo, D. Hsu, D. Conduah, R. Xu, and M. T. Abreu (2008)
J. Immunol. 180, 1886-1894
   Abstract »    Full Text »    PDF »
Selective predisposition to bacterial infections in IRAK-4 deficient children: IRAK-4 dependent TLRs are otherwise redundant in protective immunity.
C.-L. Ku, H. von Bernuth, C. Picard, S.-Y. Zhang, H.-H. Chang, K. Yang, M. Chrabieh, A. C. Issekutz, C. K. Cunningham, J. Gallin, et al. (2007)
J. Exp. Med. 204, 2407-2422
   Abstract »    Full Text »    PDF »
Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.
T. Kawagoe, S. Sato, A. Jung, M. Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi, and S. Akira (2007)
J. Exp. Med. 204, 1013-1024
   Abstract »    Full Text »    PDF »
IRAK-4 Kinase Activity Is Required for Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression.
M. Koziczak-Holbro, C. Joyce, A. Gluck, B. Kinzel, M. Muller, C. Tschopp, J. C. Mathison, C. N. Davis, and H. Gram (2007)
J. Biol. Chem. 282, 13552-13560
   Abstract »    Full Text »    PDF »
Cutting Edge: IL-1 Receptor-Associated Kinase 4 Structures Reveal Novel Features and Multiple Conformations.
A. Kuglstatter, A. G. Villasenor, D. Shaw, S. W. Lee, S. Tsing, L. Niu, K. W. Song, J. W. Barnett, and M. F. Browner (2007)
J. Immunol. 178, 2641-2645
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882