Zhou, Jie H.S. and Markham, John F. and Duffy, Ken R. and Hodgkin, Philip D. (2018) Stochastically timed competition between division and differentiation fates regulates the transition from B lymphoblast to plasma cell. Frontiers in Immunology, 9 (2053). ISSN 1664-3224

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Abstract

In response to external stimuli, naïve B cells proliferate and take on a range of fates important for immunity. How their fate is determined is a topic of much recent research, with candidates including asymmetric cell division, lineage priming, stochastic assignment, and microenvironment instruction. Here we manipulate the generation of plasmablasts from B lymphocytes in vitro by varying CD40 stimulation strength to determine its influence on potential sources of fate control. Using long-term live cell imaging, we directly measure times to differentiate, divide, and die of hundreds of pairs of sibling cells. These data reveal that while the allocation of fates is significantly altered by signal strength, the proportion of siblings identified with asymmetric fates is unchanged. In contrast, we find that plasmablast generation is enhanced by slowing times to divide, which is consistent with a hypothesis of competing timed stochastic fate outcomes. We conclude that this mechanistically simple source of alternative fate regulation is important, and that useful quantitative models of signal integration can be developed based on its principles.

Item Type:	Article
Additional Information:	This article is published under a Creative Commons Attribution 4.0 International (CC BY 4.0) License https://creativecommons.org/licenses/by/4.0/ . Cite as: Zhou JHS, Markham JF, Duffy KR and Hodgkin PD (2018) Stochastically Timed Competition Between Division and Differentiation Fates Regulates the Transition From B Lymphoblast to Plasma Cell. Front. Immunol. 9:2053. doi: 10.3389/fimmu.2018.02053 . This work was supported by the National Health and Medical Research Council via Project Grants 1010654 and 1057831, and Program Grant 1054925, and fellowships to PH and Science Foundation Ireland grant No. 12IP1263 to KD. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme Grant 361646. JZ was supported by an Australian Postgraduate Award. JM was supported by National ICT Australia (NICTA), which was funded by the Australian Research Council and the Australian Department of Broadband, Communications and the Digital Economy. We thank S. Nutt and A. Kallies for Blimp-1-GFP reporter mice.
Keywords:	B cells; anti-CD40 stimulation titration; fate regulation; lineage priming; competing stochastic timers;
Academic Unit:	Faculty of Science and Engineering > Research Institutes > Hamilton Institute
Item ID:	13078
Identification Number:	https://doi.org/10.3389/fimmu.2018.02053
Depositing User:	Dr Ken Duffy
Date Deposited:	23 Jun 2020 13:56
Journal or Publication Title:	Frontiers in Immunology
Publisher:	Frontiers Media
Refereed:	Yes
Funders:	National Health and Medical Research Council, Science Foundation Ireland (SFI), Victorian State Government Operational Infrastructure Support, Australian Government NHMRC Scheme, Australian Research Council, Australian Department of Broadband, Communications and the Digital Economy
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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