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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Kristen JohnsonJane A Skok

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-G(2) 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 cell...Continue Reading

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Citations

Feb 15, 2013·Journal of Visualized Experiments : JoVE·Julie ChaumeilJane A Skok
Jan 30, 2014·Annual Review of Immunology·Ellen V Rothenberg
Apr 23, 2016·Science·Alison GallowayMartin Turner
Apr 26, 2014·Frontiers in Immunology·Keith M HamelMarcus R Clark
Jun 18, 2016·Journal of Immunology Research·Rocio Flores-FernándezAdriana Karina Chávez-Rueda
Apr 7, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jennifer Y BarrJohn D Colgan
Oct 11, 2017·Molecular and Cellular Biology·Toru TamaharaKazuhiko Igarashi
Apr 5, 2017·Molecular and Cellular Biology·Greg A TimblinMark S Schlissel
Nov 22, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zev J GreenbergLaura G Schuettpelz
Feb 24, 2017·Wiley Interdisciplinary Reviews. RNA·Alison Galloway, Martin Turner
Oct 20, 2019·Nature Communications·Jason B WongJane A Skok
May 16, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Matthias PfeiferNiklas Feldhahn
May 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Tessa ArendsJames R Hagman
Sep 27, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Greg A Timblin, Mark S Schlissel
Mar 8, 2019·The Biochemical Journal·Georg Petkau, Martin Turner
Aug 22, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Daniel T PattonNinan Abraham
Apr 17, 2021·Trends in Immunology·Taishin AkiyamaTadashi Yamamoto
Aug 6, 2021·Frontiers in Immunology·Taishin Akiyama, Tadashi Yamamoto

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