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A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation
Nobutaka Suzuki,1Shinobu Suzuki,1*Douglas G. Millar,2Midori Unno,1Hiromitsu Hara,1Thomas Calzascia,2Sho Yamasaki,1Tadashi Yokosuka,1Nien-Jung Chen,3Alisha R. Elford,2Jun-ichiro Suzuki,4Arata Takeuchi,1Christine Mirtsos,3Denis Bouchard,3Pamela S. Ohashi,2Wen-Chen Yeh,3||Takashi Saito1||
IRAK-4 is a protein kinase that is pivotal in mediating signalsfor innate immune responses. Here, we report that IRAK-4 signalingis also essential for eliciting adaptive immune responses. Thus,in the absence of IRAK-4, in vivo T cell responses were significantlyimpaired. Upon T cell receptor stimulation, IRAK-4 is recruitedto T cell lipid rafts, where it induces downstream signals,including protein kinase C activation through the associationwith Zap70. This signaling pathway was found to be requiredfor optimal activation of nuclear factor B. Our findings suggestthat T cells use this critical regulator of innate immunityfor the development of acquired immunity, suggesting that IRAK-4may be involved in direct signal cross talk between the twosystems.
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.
Present address: Faculty of Life Sciences, University of Manchester,C-2259 Michael Smith Building, Oxford Road, Manchester M13 9PT,UK.
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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183, 568-577
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activation through the association with Zap70. This signaling pathway was found to be required for optimal activation of nuclear factor 
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. 
Present address: Faculty of Life Sciences, University of Manchester, C-2259 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. 
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. 
