@article{ad4d81fdf9084bb29d7183e5d695a9cf,
title = "Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan",
abstract = "Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying “long-lived” ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement.",
keywords = "antibody, antibody-producing cell, competition, MCL1, niche, plasma cell, plasmablast, rituximab, survival, turnover",
author = "Robinson, {Marcus James} and Zhoujie Ding and Dowling, {Mark R.} and Hill, {Danika L.} and Webster, {Rosela H.} and Craig McKenzie and Catherine Pitt and Kristy O'Donnell and Jesse Mulder and Erica Brodie and Hodgkin, {Philip D.} and Wong, {Nick C.} and Isaak Quast and Tarlinton, {David M.}",
note = "Funding Information: We thank Genentech for providing the 5D2 antibody. We thank Rory Markovic, Debbie Ramsey, and the Monash Animal Research Platform for animal welfare, husbandry, and housing assistance. We thank Steve Rockman for support with RNA-seq lab work and Celine Pattaroni and the Monash Bioinformatics Platform for bioinformatics support, advice, and access to Limma, Voom, and Degust. We thank Carole Ford and BD Biosciences for assistance with single-cell sequencing and Alfred Research Alliance FlowCore for cell sorting. This work was supported by the MASSIVE HPC facility (www.massive.org.au) and Nectar research cloud for compute infrastructure. D.M.T. was funded by the National Health and Medical Research Council (NHMRC) Australia Investigator Award (APP1175411), M.J.R. by a Monash Future Leaders Postdoctoral Fellowship, D.L.H. by an NHMRC Australia CJ Martin Early Career Fellowship (APP1139911) and the Michelson Prize from the Human Immunome Project and Michelson Medical Research Foundation, and I.Q. by an Early Postdoc Mobility Fellowship (P2ZHP3_164964) and an Advanced Postdoc Mobility Fellowship (P300PA_177893) provided by the Swiss National Science Foundation and an NHMRC Australia Peter Doherty Early Career Fellowship (APP1145136). This work was supported by an NHMRC project grant APP1146617 awarded to D.M.T. and I.Q. and an NHMRC Ideas Grant APP1185294 awarded to M.J.R. I.Q. and E.B. Conceptualization, D.M.T.; methodology, D.M.T. M.J.R. K.O. N.C.W. C.P. P.D.H. and D.L.H.; validation, K.O. C.P. and Z.D.; formal analysis, M.J.R. Z.D. M.R.D. P.D.H. C.M. and D.L.H.; investigation, M.J.R. Z.D. C.P. R.H.W. E.B. and K.O.; writing—original draft, M.J.R. and D.M.T.; writing—review and editing, M.J.R. M.R.D. R.H.W. P.D.H. J.M. Z.D. I.Q. E.B. D.L.H. and D.M.T.; visualization, M.J.R. Z.D. D.L.H. M.R.D. P.D.H. I.Q. and C.M.; supervision, D.M.T.; project administration, D.M.T. and M.J.R. funding acquisition, D.M.T. I.Q. and M.J.R. The authors declare no competing interests. Funding Information: We thank Genentech for providing the 5D2 antibody. We thank Rory Markovic, Debbie Ramsey, and the Monash Animal Research Platform for animal welfare, husbandry, and housing assistance. We thank Steve Rockman for support with RNA-seq lab work and Celine Pattaroni and the Monash Bioinformatics Platform for bioinformatics support, advice, and access to Limma, Voom, and Degust. We thank Carole Ford and BD Biosciences for assistance with single-cell sequencing and Alfred Research Alliance FlowCore for cell sorting. This work was supported by the MASSIVE HPC facility ( www.massive.org.au ) and Nectar research cloud for compute infrastructure. D.M.T. was funded by the National Health and Medical Research Council (NHMRC) Australia Investigator Award ( APP1175411 ), M.J.R. by a Monash Future Leaders Postdoctoral Fellowship , D.L.H. by an NHMRC Australia CJ Martin Early Career Fellowship ( APP1139911 ) and the Michelson Prize from the Human Immunome Project and Michelson Medical Research Foundation , and I.Q. by an Early Postdoc Mobility Fellowship ( P2ZHP3_164964 ) and an Advanced Postdoc Mobility Fellowship ( P300PA_177893 ) provided by the Swiss National Science Foundation and an NHMRC Australia Peter Doherty Early Career Fellowship ( APP1145136 ). This work was supported by an NHMRC project grant APP1146617 awarded to D.M.T. and I.Q. and an NHMRC Ideas Grant APP1185294 awarded to M.J.R., I.Q., and E.B. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jul,
day = "11",
doi = "10.1016/j.immuni.2023.04.015",
language = "English",
volume = "56",
pages = "1596--1612.e4",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "7",
}
