Impaired lymphocyte development and function in Clast5/Stra13/DEC1‐transgenic mice

• Published in: European journal of immunology 2004-05, Vol.34 (5), p.1322-1332
• Main Authors: Seimiya, Mika, Wada, Akihiko, Kawamura, Kiyoko, Sakamoto, Akemi, Ohkubo, Yusuke, Okada, Seiji, Hatano, Masahiko, Tokuhisa, Takeshi, Watanabe, Takeshi, Saisho, Hiromitsu, Tagawa, Masatoshi, O‐Wang, Jiyang
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; B-Lymphocytes - immunology; B-Lymphocytes - physiology; Basic Helix-Loop-Helix Transcription Factors; B lymphocyte; Cell Differentiation - physiology; Cellular proliferation; Disease Models, Animal; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; IL‐7; Interleukin-7 - metabolism; Mice; Mice, Transgenic; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Thymus Gland - physiology; Transcription factor; T lymphocyte
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324700

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 theprogenitor 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 ells. 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, thedevelopment 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.