Essential function for the kinase TAK1 in innate and adaptive immune responses

Shintaro Sato^1, 7, Hideki Sanjo^2, 3, 7, Kiyoshi Takeda⁴, Jun Ninomiya-Tsuji⁵, Masahiro Yamamoto², Taro Kawai¹, Kunihiro Matsumoto⁶, Osamu Takeuchi^1, 2 & Shizuo Akira^1, 2

¹  Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, Suita, Osaka, 565-0871, Japan.

²  Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.

³  Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.

⁴  Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

⁵  Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633, USA.

⁶  Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, 464-8602, Japan.

⁷  These authors contributed equally to this work.

Transforming growth factor-–activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1 and tumor necrosis factor. Studies of mice with B cell–specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell–specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-B and mitogen-activated protein kinases in response to interleukin 1, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-B but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.

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