STAT5 activation underlies IL7 receptor-dependent B cell development

J Immunol. 2004 Apr 15;172(8):4770-8. doi: 10.4049/jimmunol.172.8.4770.

Abstract

Signals initiated by the IL7R are required for B cell development. However, the roles that distinct IL7R-induced signaling pathways play in this process remains unclear. To identify the function of the Raf and STAT5 pathways in IL7R-dependent B cell development, we used transgenic mice that express constitutively active forms of Raf (Raf-CAAX) or STAT5 (STAT5b-CA) throughout lymphocyte development. Both Raf-CAAX and STAT5b-CA mice exhibit large increases in pro-B cells. However, crossing the Raf-CAAX transgene onto the IL7R(-/-) background fails to rescue B cell development. In contrast, STAT5 activation selectively restores B cell expansion in IL7R(-/-) mice. Notably, the expansion of pro-B cells in STAT5b-CA mice correlated with an increase in cyclin D2, pim-1, and bcl-x(L) expression, suggesting that STAT5 directly affects pro-B cell proliferation and survival. In addition, STAT5 activation also restored B cell differentiation in IL7R(-/-) mice as determined by 1) the restoration of V(H) Ig gene rearrangement and 2) the appearance of immature and mature B cell subsets. These findings establish STAT5 as the key player entraining B cell development downstream of the IL7R.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Division / genetics
  • Cell Division / immunology
  • Cell Survival / genetics
  • Cell Survival / immunology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / immunology
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Milk Proteins*
  • Proto-Oncogene Proteins c-raf / biosynthesis
  • Proto-Oncogene Proteins c-raf / genetics
  • Receptors, Interleukin-7 / deficiency
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / physiology*
  • STAT5 Transcription Factor
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Trans-Activators / biosynthesis
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • DNA-Binding Proteins
  • Milk Proteins
  • Receptors, Interleukin-7
  • STAT5 Transcription Factor
  • Stat5b protein, mouse
  • Trans-Activators
  • Proto-Oncogene Proteins c-raf