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International Immunology Advance Access originally published online on August 8, 2008
International Immunology 2008 20(10):1299-1311; doi:10.1093/intimm/dxn084
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Altered cellular immunity in transgenic mice with T cell-specific expression of human D4-guanine diphosphate-dissociation inhibitor (D4-GDI)

Kensuke Kondoh1,2,3, Yuji Nakata1,2,4, Takashi Yamaoka5, Mitsuo Itakura5, Mutsumi Hayashi1,2, Kohji Yamada1, Jun-ichi Hata1,6 and Taketo Yamada1

1 Department of Pathology
2 Department of Pediatrics, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
3 Department of Pediatrics, St Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kanagawa 216-8511, Japan
4 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
5 Otsuka Department of Clinical and Molecular Nutrition, Tokushima University School of Medicine, Tokushima, Japan
6 National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

Correspondence to: K. Kondoh; E-mail: kensuke-k{at}marianna-u.ac.jp

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.

Keywords: cytoskeletal organization, cytozoic pathogens, leukemic cells, proliferation, Rho

Transmitting editor: E. Viver

Received 20 August 2007, accepted 2 July 2008.


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