Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease

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  • Atsushi Tanaka
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Shinji Maeda
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Takashi Nomura
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Mara Anais Llamas-Covarrubias
    Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 5
  • Satoshi Tanaka
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Lin Jin
    Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 5
  • Ee Lyn Lim
    Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 2
  • Hiromasa Morikawa
    Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 2
  • Yohko Kitagawa
    Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 2
  • Shuji Akizuki
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Yoshinaga Ito
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Chihiro Fujimori
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Keiji Hirota
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Tosei Murase
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Motomu Hashimoto
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Junichi Higo
    Institute for Protein Research, Osaka University, Suita, Japan 7
  • Rose Zamoyska
    Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh, UK 8
  • Ryuzo Ueda
    Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan 9
  • Daron M. Standley
    Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 5
  • Noriko Sakaguchi
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1
  • Shimon Sakaguchi
    Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 1

抄録

<jats:p>Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.</jats:p>

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