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

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Author

  • Erica Manesso
  • Vijay Chickarmane
  • Hao Yuan Kueh
  • Ellen V Rothenberg
  • Carsten Peterson

Summary, in English

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.

Publishing year

2013

Language

English

Publication/Series

Journal of the Royal Society Interface

Volume

10

Issue

78

Document type

Journal article

Publisher

The Royal Society of Canada

Topic

  • Biophysics

Status

Published

ISBN/ISSN/Other

  • ISSN: 1742-5662