Altered cellular immunity in transgenic mice with T cell-specific expression of human D4-guanine diphosphate-dissociation inhibitor (D4-GDI).
D4-GDI, a Rho guanosine diphosphate (GDP) dissociation inhibitor, is preferentially expressed in hematopoietic tissues and binds to a small GTP-binding protein, Rho, and inhibits GDP dissociation from Rho. We identified point mutations in the D4-GDI gene in human leukemic cells. We therefore investigated the functions of D4-GDI and mutated D4-GDI in T cells. Transgenic mice (Tg) harboring human wild-type and mutant D4-GDI transgenes driven by the lck promoter were generated. Cellular immunity responses against cytozoic pathogens were examined. The cytoskeletal organization in the CD3+T cells and the proliferation of splenocytes by Con A were investigated in both Tg and littermates (LMs). Granuloma formation by bacille Calmette-Guerin was impaired in the wild-type D4-GDI Tg. On the other hand, the number of granulomas of the mutated D4-Tg was significantly higher. Infection with Listeria was more rapidly fatal to wild-type D4-GDI Tg than to LMs, while the survival of mutated D4-GDI Tg was prolonged. The CD3+T cells in wild-type D4-GDI Tg showed an impairment in the formation of stress fibers on anti-CD3 antibody-coated plates, whereas the cytoskeletal organization in CD3+T cells of the mutated D4-GDI Tg was augmented. The proliferation of splenocytes after Con A stimulation was higher in the mutated D4-GDI Tg than in the LMs. D4-GDI may have important functions, such as induction of T cell migration, adhesion and/or proliferation in inflammatory foci, in cellular immunity responses to cytozoic pathogens.
Kondoh
Kensuke
K
Department of Pathology, Keio University School of Medicine, Shinjuku-ku,Tokyo 160-8582, Japan. kensuke-k@marianna-u.ac.jp
Nakata
Yuji
Y
Yamaoka
Takashi
T
Itakura
Mitsuo
M
Hayashi
Mutsumi
M
Yamada
Kohji
K
Hata
Jun-ichi
J
Yamada
Taketo
T
D000818:Animals; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000032:analysis; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D008087:Listeria / Q000472:pathogenicity; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology / Q000472:pathogenicity; D009928:Organ Specificity; D017354:Point Mutation; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019076:Transgenes / Q000235:genetics / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C569658:ARHGDIB protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D004247:DNA; D020741:rho GTP-Binding Proteins