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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}rcai.riken.jp (T.S.); wyeh{at}uhnres.utoronto.ca (W.-C.Y.)


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