Attenuation of IL-7 receptor signaling is not required for allelic exclusion.
Allelic exclusion prevents pre-B cells from generating more than one functional H chain, thereby ensuring the formation of a unique pre-BCR. The signaling processes underlying allelic exclusion are not clearly understood. IL-7R-dependent signals have been clearly shown to regulate the accessibility of the Ig H chain locus. More recent work has suggested that pre-BCR-dependent attenuation of IL-7R signaling returns the H chain loci to an inaccessible state; this process has been proposed to underlie allelic exclusion. Importantly, this model predicts that preventing pre-BCR-dependent down-regulation of IL-7R signaling should interfere with allelic exclusion. To test this hypothesis, we made use of transgenic mice that express a constitutively active form of STAT5b (STAT5b-CA). STAT5b-CA expression restores V(D)J recombination in IL-7R(-/-) B cells, demonstrating that IL-7 regulates H chain locus accessibility and V(D)J recombination via STAT5 activation. To examine the effects of constitutively active STAT5b on allelic exclusion, we crossed STAT5b-CA mice (which express the IgM(b) allotype) to IgM(a) allotype congenic mice. We found no difference in the percentage of IgM(a)/IgM(b)-coexpressing B cells in STAT5b-CA vs littermate control mice; identical results were observed when crossing STAT5b-CA mice with hen egg lysozyme (HEL) H chain transgenic mice. The HEL transgene enforces allelic exclusion, preventing rearrangement of endogenous H chain genes; importantly, rearrangement of endogenous H chain genes was suppressed to a similar degree in STAT5b-CA vs HEL mice. Thus, attenuation of IL-7R/STAT5 signaling is not required for allelic exclusion.
Will
Wynette M
WM
Department of Laboratory Medicine and Pathology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Aaker
Joshua D
JD
Burchill
Matthew A
MA
Harmon
Ian R
IR
O'Neil
Jennifer J
JJ
Goetz
Christine A
CA
Hippen
Keli L
KL
Farrar
Michael A
MA
D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism
D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse