Journal article
Lineage tracing reveals B cell antibody class switching is stochastic, cell-autonomous, and tuneable
MB Horton, HC Cheon, KR Duffy, D Brown, SH Naik, C Alvarado, JR Groom, S Heinzel, PD Hodgkin
Immunity | Published : 2022
Abstract
To optimize immunity to pathogens, B lymphocytes generate plasma cells with functionally diverse antibody isotypes. By lineage tracing single cells within differentiating B cell clones, we identified the heritability of discrete fate controlling mechanisms to inform a general mathematical model of B cell fate regulation. Founder cells highly influenced clonal plasma-cell fate, whereas class switch recombination (CSR) was variegated within clones. In turn, these CSR patterns resulted from independent all-or-none expression of both activation-induced cytidine deaminase (AID) and IgH germline transcription (GLT), with the latter being randomly re-expressed after each cell division. A stochastic..
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Awarded by Horizon 2020 Framework Programme
Funding Acknowledgements
We would like to thank all members of the Hodgkin and Naik laboratories for thoughtful discussions and suggestions; D. Tarlinton and D. Gray for helpful feedback on the manuscript; S. Nutt and J. Tellier for the Aicda- Cre mice and discussion of experiments; the Flow Cytometry Facility and Single Cell Open Research Endeavour at WEHI for technical assistance; J. Roco at JCSMR for discussion and technical advice. Funding: this work was supported by the Victorian State Government Operational Infrastructure Support and the Australian National Health and Medical Research Council (NHMRC) Independent Research Institutes Infrastructure Support Scheme (361646) and the following NHMRC grants: Project Grant GNT1164800 to P.D.H and S.H; Investigator Grant GNT1176588 to P.D.H; Ideas (GNT1182649) and Project (GNT1137989) grants to J.R.G; GNT1062820, GNT1100033, GNT1101378, GNT1124812 and GNT 1145184 to S.H.N. Funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodow- ska-Curie grant agreement no. 764698 supported K.R.D and H.C.C. This publication has emanated from research supported in part by a research grant from the Science Foundation Ireland (SFI) under grant number 16/RI/3399.