STAT5 activation underlies IL7 receptor-dependent B cell development.
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.
Goetz
Christine A
CA
Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Harmon
Ian R
IR
O'Neil
Jennifer J
JJ
Burchill
Matthew A
MA
Farrar
Michael A
MA
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D019908:Proto-Oncogene Proteins c-raf