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東京理科大学生命科学研究所
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1)
Dr. Klaus Rajewsky
Professor CBR Institute for Biomedical Research
Harvard Medical School Boston

タイトル:"NFkappaB signaling in normal and malignant B cell development"

日時:2006年4月19日(水)10:30~12:00
場所:東京理科大学生命科学研究所2階大講義室


2)
Dr. Bernard Malissen
Research Director Centre d’Immunologie de Marseille-Luminy&s_comma; Case 906&s_comma; 13288 Marseille Cedex 9&s_comma; France

日時:2006年4月24日(月)15:00~16:30
場所:東京理科大学生命科学研究所2階大講義室

タイトル:"Role of the LAT adaptor in T cell development and Th1/Th2 commitment"

The transduction cassettes operated by the pre-TCR&s_comma; the αβ-&s_comma; and the γδ-TCR complexes share many functional components. Among them&s_comma; the adaptor molecule LAT (linker for activation of T cells) plays a crucial role in that it coordinates the assembly of signaling complexes through multiple tyrosine residues within its intracytoplasmic segment. Mice deficient in LAT or having a mutation of the four COOH-terminal tyrosines residues revealed that LAT is essential for the function of the pre-TCR. A mutation that replaced tyrosine 136 of LAT with a phenylalanine caused a partial block in αβ T cell development. However&s_comma; over time&s_comma; the mice developed a fatal lymphoproliferation disorder featuring an overabundance of polyclonal CD4+ T cells that chronically produced type 2 cytokines. This exaggerated Th2 differentiation caused tissue eosinophilia and massive maturation of plasma cells secreting IgE and IgG1. These analyses suggest that&s_comma; although the LAT Y136 residue has a positive function during αβ T cell development&s_comma; it has&s_comma; in addition&s_comma; an inhibitory function that is critical for the terminal differentiation and homeostasis of CD4 T cells.. Mice with a compound mutation where tyrosines 175&s_comma; 195 and 235 of LAT were replaced with phenylalanine showed an expansion of pathogenic γδ T cells that spontaneously deploy a TH2-like effector program.
These data reveal a remarkable convergence in the developmental sequence and functional phenotype induced in the γδ and αβ lineages by two distinct mutations in the LAT adaptor. Although each of these mutations is expected to disconnect LAT from unique intracellular signaling pathways&s_comma; they result in the development and expansion of populations of γδ and of CD4+ αβ T cells that both deploy a TH2-like effector program and trigger a TH2-type disorder. Therefore&s_comma; the occurrence of such conspicuously similar lymphoproliferative disorders shows that LAT not only positively regulates T cell development&s_comma; but also negatively regulates peripheral T cell homeostasis. As will be discussed&s_comma; the available data underscore the existence of an immunopathology proper to defective LAT signalosome.


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連絡先:
北村大介
東京理科大学生命科学研究所
分子生物学研究部門
〒278-0022 千葉県野田市山崎2669
Tel: 04-7121-4071 (lab:-4072)
Fax:04-7121-4079
E-mail: kitamura@rs.noda.tus.ac.jp


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