T cell-specific gene targeting reveals that alpha4 is required for early T cell development.
Alpha4-mediated signaling is involved in a variety of functions in mammalian cells. To determine whether this is true for immunocompetent cells, we generated mutant (Lck-alpha4-) mice in which the alpha4 gene was deleted in a T cell-specific manner using the Cre/loxP system. These mice showed impaired early T cell development. Thymi at most ages were small and their architecture was disorganized. This defect was not due to increased thymocyte apoptosis but to decreased cell proliferation. T cell development was found to be severely arrested at the CD4/CD8 double-negative 3 stage and the thymus contained very few double-positive or single-positive (SP) mature thymocytes. The mutant thymocytes showed impaired proliferative responses to anti-CD3 monoclonal antibody (mAb) stimulation or to the cytokines IL-2, IL-1 or TNF. In the spleen, the numbers of mature SP T cells were decreased and their proliferative responses to anti-CD3 plus IL-2 or to anti-CD28 mAb were impaired. A severe impairment of CD3-induced expression of CD25 was also observed. These data suggest that alpha4 plays a critical role in the proliferation of thymocytes, which is necessary for early T cell development.
Hua
Ding Rong
DR
Department of Immunology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Inui
Seiji
S
Yamashita
Takeshi
T
Maeda
Kazuhiko
K
Takagi
Katsumasa
K
Takeda
Junji
J
Sakaguchi
Nobuo
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017252:CD3 Complex / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D018390:Gene Targeting; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018832:Molecular Chaperones; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C092377:Igbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins