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Attenuation of IL-7 Receptor Signaling Is Not Required for Allelic Exclusion¹

Wynette M. Will^*, Joshua D. Aaker^*, Matthew A. Burchill^*, Ian R. Harmon^*, Jennifer J. O’Neil^*, Christine A. Goetz^*, Keli L. Hippen and Michael A. Farrar^2,*

^* Department of Laboratory Medicine and Pathology and Department of Medicine, Center for Immunology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455

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.

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