Impaired lymphocyte development and function in Clast5/Stra13/DEC1-transgenic mice.
Clast5/Stra13/DEC1 is a member of the helix-loop-helix family of transcriptional repressors. We have previously shown that Clast5 is rapidly down-regulated upon B cell activation and its overexpression inhibits cell cycle progression in B lymphoma cells. In the present study, we show that Clast5 expression is developmentally regulated during B cell differentiation, being expressed at the progenitor B cells, down-regulated at the precursor B cells, elevated in immature and mature resting B lymphocytes, and down-regulated again in germinal center B cells. To investigate the function of Clast5 in regulating lymphocyte development, we have generated transgenic mice expressing Clast5 in B- and T-lineage cells (Clast5-Tg). Clast5-Tg mice grew and bred normally but their spleen and thymus cellularity was reduced compared with control littermates. The development of B cells in the bone marrow and T cells in the thymus was impaired, with the expansion of progenitor B and T cells most strongly affected. The frequency of IL-7-responsive cells in the bone marrow of Clast5-Tg mice was reduced by >80% and their proliferative response to IL-7 was also compromised. Mature B cells from Clast5-Tg mice were hyporesponsive to antigen receptor cross-linking and exhibited mild reduction in the proliferative response to CD40 ligation or lipopolysaccharide stimulation. Moreover, the development of germinal center B cells and antibody production against a T-dependent antigen were reduced in Clast5-Tg mice. These results reveal a critical role for Clast5/Stra13/DEC1 in negatively regulating lymphocyte development and function in vivo.
Seimiya
Mika
M
Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan.
Wada
Akihiko
A
Kawamura
Kiyoko
K
Sakamoto
Akemi
A
Ohkubo
Yusuke
Y
Okada
Seiji
S
Hatano
Masahiko
M
Tokuhisa
Takeshi
T
Watanabe
Takeshi
T
Saisho
Hiromitsu
H
Tagawa
Masatoshi
M
O-Wang
Jiyang
J
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology*; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D015851:Interleukin-7; C491539:Bhlhe40 protein, mouse