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Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence.

Manesso, Erica LU ; Chickarmane, Vijay; Kueh, Hao Yuan; Rothenberg, Ellen V and Peterson, Carsten LU (2013) In Journal of the Royal Society Interface 10(78).
Abstract
Bone-marrow-derived progenitors must continually enter the thymus of an adult mouse to sustain T-cell homeostasis, yet only a few input cells per day are sufficient to support a yield of 5 × 10(7) immature T-cells per day and an eventual output of 1-2 × 10(6) mature cells per day. While substantial progress has been made to delineate the developmental pathway of T-cell lineage commitment, still little is known about the relationship between differentiation competence and the remarkable expansion of the earliest (DN1 stage) T-cell progenitors. To address this question, we developed computational models where the probability to progress to the next stage (DN2) is related to division number. To satisfy differentiation kinetics and overall... (More)
Bone-marrow-derived progenitors must continually enter the thymus of an adult mouse to sustain T-cell homeostasis, yet only a few input cells per day are sufficient to support a yield of 5 × 10(7) immature T-cells per day and an eventual output of 1-2 × 10(6) mature cells per day. While substantial progress has been made to delineate the developmental pathway of T-cell lineage commitment, still little is known about the relationship between differentiation competence and the remarkable expansion of the earliest (DN1 stage) T-cell progenitors. To address this question, we developed computational models where the probability to progress to the next stage (DN2) is related to division number. To satisfy differentiation kinetics and overall cell yield data, our models require that adult DN1 cells divide multiple times before becoming competent to progress into DN2 stage. Our findings were subsequently tested by in vitro experiments, where putative early and later-stage DN1 progenitors from the thymus were purified and their progression into DN2 was measured. These experiments showed that the two DN1 sub-populations divided with similar rates, but progressed to the DN2 stage with different rates, thus providing experimental evidence that DN1 cells increase their commitment probability in a cell-intrinsic manner as they undergo cell division. Proliferation-linked shifts in eligibility of DN1 cells to undergo specification thus control kinetics of T-cell generation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the Royal Society Interface
volume
10
issue
78
publisher
The Royal Society of Canada
external identifiers
  • wos:000311939400034
  • pmid:23152106
  • scopus:84871284932
ISSN
1742-5662
DOI
10.1098/rsif.2012.0774
language
English
LU publication?
yes
id
80f59bf1-4175-4502-98ba-61071cf63432 (old id 3218958)
date added to LUP
2012-12-13 14:30:31
date last changed
2019-07-30 01:46:45
@article{80f59bf1-4175-4502-98ba-61071cf63432,
  abstract     = {Bone-marrow-derived progenitors must continually enter the thymus of an adult mouse to sustain T-cell homeostasis, yet only a few input cells per day are sufficient to support a yield of 5 × 10(7) immature T-cells per day and an eventual output of 1-2 × 10(6) mature cells per day. While substantial progress has been made to delineate the developmental pathway of T-cell lineage commitment, still little is known about the relationship between differentiation competence and the remarkable expansion of the earliest (DN1 stage) T-cell progenitors. To address this question, we developed computational models where the probability to progress to the next stage (DN2) is related to division number. To satisfy differentiation kinetics and overall cell yield data, our models require that adult DN1 cells divide multiple times before becoming competent to progress into DN2 stage. Our findings were subsequently tested by in vitro experiments, where putative early and later-stage DN1 progenitors from the thymus were purified and their progression into DN2 was measured. These experiments showed that the two DN1 sub-populations divided with similar rates, but progressed to the DN2 stage with different rates, thus providing experimental evidence that DN1 cells increase their commitment probability in a cell-intrinsic manner as they undergo cell division. Proliferation-linked shifts in eligibility of DN1 cells to undergo specification thus control kinetics of T-cell generation.},
  articleno    = {20120774},
  author       = {Manesso, Erica and Chickarmane, Vijay and Kueh, Hao Yuan and Rothenberg, Ellen V and Peterson, Carsten},
  issn         = {1742-5662},
  language     = {eng},
  number       = {78},
  publisher    = {The Royal Society of Canada},
  series       = {Journal of the Royal Society Interface},
  title        = {Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence.},
  url          = {http://dx.doi.org/10.1098/rsif.2012.0774},
  volume       = {10},
  year         = {2013},
}