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

Eur J Immunol. 2004 May;34(5):1322-32. doi: 10.1002/eji.200324700.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / physiology*
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation / physiology*
  • Disease Models, Animal
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Interleukin-7 / metabolism
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • Thymus Gland / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • Homeodomain Proteins
  • Interleukin-7