IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle

Kristen Johnson, Julie Chaumeil, Mariann Micsinai, Joy M.H. Wang, Laura B. Ramsey, Gisele V. Baracho, Robert C. Rickert, Francesco Strino, Yuval Kluger, Michael A. Farrar, Jane A. Skok

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Ag receptor diversity involves the introduction of DNA double-stranded breaks during lymphocyte development. To ensure fidelity, cleavage is confined to the G 0-G 1 phase of the cell cycle. One established mechanism of regulation is through periodic degradation of the RAG2 recombinase protein. However, there are additional levels of protection. In this paper, we show that cyclical changes in the IL-7R signaling pathway functionally segregate pro-B cells according to cell cycle status. In consequence, the level of a downstream effector of IL-7 signaling, phospho-STAT5, is inversely correlated with cell cycle expression of Rag, a key gene involved in recombination. Higher levels of phopho-STAT5 in S-G2 correlate with decreased Rag expression and Rag relocalization to pericentromeric heterochromatin. These cyclical changes in transcription and locus repositioning are ablated upon transformation with v-Abl, which renders STAT5 constitutively active across the cell cycle. We propose that this activity of the IL-7R/ STAT5 pathway plays a critical protective role in development, complementing regulation of RAG2 at the protein level, to ensure that recombination does not occur during replication. Our data, suggesting that pro-B cells are not a single homogeneous population, explain inconsistencies in the role of IL-7 signaling in regulating Igh recombination.

Original languageEnglish (US)
Pages (from-to)6084-6092
Number of pages9
JournalJournal of Immunology
Volume188
Issue number12
DOIs
StatePublished - Jun 15 2012

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    Johnson, K., Chaumeil, J., Micsinai, M., Wang, J. M. H., Ramsey, L. B., Baracho, G. V., Rickert, R. C., Strino, F., Kluger, Y., Farrar, M. A., & Skok, J. A. (2012). IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle. Journal of Immunology, 188(12), 6084-6092. https://doi.org/10.4049/jimmunol.1200368