ArticleProceedings of the National Academy of Sciences of the United States of America2011
Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 44 citations in OpenAlex.
- Quantitative systems pharmacology model of B cell immune response in mouse.Frontiers in immunology · 2026Article
- Homeostatic regulation of renewing tissue cell populations via crowding control: stability, robustness and quasi-dedifferentiation.Journal of mathematical biology · 2024Article
- Small spleen peptides prevent development of psoriatic arthritis via restoration of peripheral tolerance.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart.Frontiers in immunology · 2022Article
- Regulation of T Cell Responses by Nano-Hydroxyapatite to Mediate the Osteogenesis.Frontiers in bioengineering and biotechnology · 2022Article
- Article
- Prediction of PD-L1 inhibition effects for HIV-infected individuals.PLoS computational biology · 2019Article
- How a well-adapting immune system remembers.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Regulation of T cell expansion by antigen presentation dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Immunological Paradigms, Mechanisms, and Models: Conceptual Understanding Is a Prerequisite to Effective Modeling.Frontiers in immunology · 2019Review
- Variable setpoint as a relaxing component in physiological control.Physiological reports · 2017Article
- Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy.Cancer research · 2017Article
- Mechanisms of cell division as regulators of acute immune response.Systems and synthetic biology · 2014Review
- Interactions and tradeoffs between cell recruitment, proliferation, and differentiation affect CNS regeneration.Biophysical journal · 2014Article
- Minimizing the risk of cancer: tissue architecture and cellular replication limits.Journal of the Royal Society, Interface · 2013Article
- Quantifying T lymphocyte turnover.Journal of theoretical biology · 2013Article
- Antigen-stimulated CD4 T cell expansion can be limited by their grazing of peptide-MHC complexes.Journal of immunology (Baltimore, Md. : 1950) · 2013Article
- Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence.Journal of the Royal Society, Interface · 2013Article
- Stem cell control, oscillations, and tissue regeneration in spatial and non-spatial models.Frontiers in oncology · 2013Article
- Article
Corrections and comments
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Authors and funding
9 authors at 7 institutions in 3 countries.
Funding
Abstract
The mechanisms regulating clonal expansion and contraction of T cells in response to immunization remain to be identified. A recent study established that there was a log-linear relation between CD4 T-cell precursor number (PN) and factor of expansion (FE), with a slope of ∼-0.5 over a range of 3-30,000 precursors per mouse. The results suggested inhibition of precursor expansion either by competition for specific antigen-presenting cells or by the action of other antigen-specific cells in the same microenvironment as the most likely explanation. Several molecular mechanisms potentially accounting for such inhibition were examined and rejected. Here we adopt a previously proposed concept, "feedback-regulated balance of growth and differentiation," and show that it can explain the observed findings. We assume that the most differentiated effectors (or memory cells) limit the growth of less differentiated effectors, locally, by increasing the rate of differentiation of the latter cells in a dose-dependent manner. Consequently, expansion is blocked and reversed after a delay that depends on initial PN, accounting for the dependence of the peak of the response on that number. We present a parsimonious mathematical model capable of reproducing immunization response kinetics. Model definition is achieved in part by requiring consistency with available BrdU-labeling and carboxyfluorescein diacetate succinimidyl ester (CFSE)-dilution data. The calibrated model correctly predicts FE as a function of PN. We conclude that feedback-regulated balance of growth and differentiation, although awaiting definite experimental characterization of the hypothetical cells and molecules involved in regulation, can explain the kinetics of CD4 T-cell responses to antigenic stimulation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.