Attenuation of IL-7 receptor signaling is not required for allelic exclusion

Wynette M. Will, Joshua D. Aaker, Matthew A. Burchill, Ian R. Harmon, Jennifer J. O'Neil, Christine A. Goetz, Keli L. Hippen, Michael A. Farrar

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8 Scopus citations

Abstract

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 IgMb allotype) to IgMa allotype coagenic mice. We found no difference in the percentage of IgMa/IgMb-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.

Original languageEnglish (US)
Pages (from-to)3350-3355
Number of pages6
JournalJournal of Immunology
Volume176
Issue number6
DOIs
StatePublished - Mar 15 2006

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    Will, W. M., Aaker, J. D., Burchill, M. A., Harmon, I. R., O'Neil, J. J., Goetz, C. A., Hippen, K. L., & Farrar, M. A. (2006). Attenuation of IL-7 receptor signaling is not required for allelic exclusion. Journal of Immunology, 176(6), 3350-3355. https://doi.org/10.4049/jimmunol.176.6.3350