T cell development in the thymus: From periodic seeding to constant output

Cai, Anna Q.; Landman, Kerry A.; Hughes, Barry D.; Witt, Colleen M.

doi:10.1016/j.jtbi.2007.07.028

Cited by 11 publications

(13 citation statements)

References 28 publications

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“…Moreover, the clinical importance of understanding how the body maintains its supply of crucial immune cells as well as the ways thymocytopoiesis may go wrong and turn into malignant lymphomas, have inspired the development of many mathematical models [4][5][6][7][8]. A number of models have addressed the dynamical features of the differentiation stages, for instance with studies on the way a periodic thymic colonization by progenitor cells guarantees the homeostasis of thymocyte population [4] or on the recovery from transient depletion of dividing T-cells in mice [5]. Alternatively, other models have attempted to describe the interactions of developing thymocytes with cellular and extracellular elements of the thymus, e.g.…”

Section: Introductionmentioning

confidence: 99%

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

Manesso

Chickarmane

Kueh

et al. 2013

J. R. Soc. Interface.

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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 Â 10 7 immature T-cells per dayand an eventual output of 1-2 Â 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.

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Section: Introductionmentioning

confidence: 99%

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

Manesso

Chickarmane

Kueh

et al. 2013

J. R. Soc. Interface.

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“…Fewer than 10 precursor cells home from the BM to the thymus each day (25)(26)(27). These immigrants to the thymus will divide and differentiate, giving rise to a wave of T cell development lasting ∼4 wk (28,29). At very low levels of chimerism (i.e., the proportion of tracked cells among bone marrow precursors in mixed hematopoietic chimeras), these tracked precursors will colonize the thymus only very infrequently, potentially giving rise to distinguishable waves of developing T cells.…”

mentioning

confidence: 99%

The Thymic Niche Does Not Limit Development of the Naturally Diverse Population of Mouse Regulatory T Lymphocytes

Romagnoli

Dooley

Enault

et al. 2012

The Journal of Immunology

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Thymus-derived CD4+Foxp3+ regulatory T lymphocytes (Tregs) play a central role in the suppression of immune responses to self-antigens and thus avoid autoimmune disorders. It remains unclear if the specialized thymic niche controls the number of differentiating Tregs. We investigated development of murine Tregs from precursors expressing the naturally very large repertoire of TCRs. By analyzing their developmental kinetics, we observed that differentiating Tregs dwell in the thymus ∼1 d longer than their conventional T cell counterparts. By generating hematopoietic chimeras with very low proportions of trackable precursors, we could follow individual waves of developing T cells in the thymus. We observed strongly increased proportions of Tregs at the end of the waves, confirming that these cells are the last to leave the thymus. To assess whether the thymic niche limits Treg development, we generated hematopoietic chimeras in which very few T cell precursors could develop. The substantial increase in the proportion of Tregs we found in these mice suggested a limiting role of the thymic niche; however, this increase was accounted for entirely by the prolonged thymic dwell time of Tregs. We conclude that, when precursors express a naturally diverse TCR repertoire, the thymic niche does not limit differentiation of Tregs.

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“…[17] had developed the first kinetic model of the thymocyte development using ordinary differential equations (ODEs) [18]. Since this pioneering work, kinetic models of the thymopoiesis have been progressively refined by taking into account of the detailed cellularity and developmental states of the thymocytes and by incorporating different experimental conditions [19][20][21][22][23].…”

Section: Main Textmentioning

confidence: 99%

“…By combining mathematical models with such quantitative data, dynamic aspects of thymopoiesis have been distilled in the forms of more detailed kinetic information, e.g., rates of proliferation, death, and differentiation [12,16]. Mehr et al[17] had developed the first kinetic model of the thymocyte development using ordinary differential equations (ODEs) [18]. Since this pioneering work, kinetic models of the thymopoiesis have been progressively refined by taking into account of the detailed cellularity and developmental states of the thymocytes and by incorporating different experimental conditions [19][20][21][22][23].Nevertheless, the previous works have focused only on the thymocytes.…”

mentioning

confidence: 99%

Quantitative Analysis Reveals Reciprocal Regulations Underlying Recovery Dynamics of Thymocytes and Thymic Environment

Kaneko

Tateishi

Miyao

et al. 2018

Preprint

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Thymic crosstalk, a set of reciprocal regulations between thymocytes and thymic environment, is relevant for orchestrating the appropriate development of thymocytes as well as the recovery of the thymus from various exogenous insults. Nevertheless, the dynamic and regulatory aspects of the thymic crosstalk have not yet been clarified. In this work, we inferred the interactions shaping the thymic crosstalk and its resultant dynamics between the thymocytes and the thymic epithelial cells (TECs) by quantitative analysis and modelling of the recovery dynamics induced by irradiation. The analysis identified regulatory interactions consistent with the known molecular evidence and revealed their dynamic roles in the recovery process. Moreover, the analysis also predicted, and a subsequent experiment verified a new regulation of CD4+CD8+ double positive (DP) thymocytes, which temporarily increases their proliferation rate upon the decrease in their population size. Our model established the pivotal step towards a dynamic understanding of the thymic crosstalk as a regulatory network system. Main textThe thymus is an organ responsible for producing a large part of T cells with appropriate repertoires [1]. Nevertheless, it is relatively sensitive to insults by stress, virus infection, radiation, and other extra stimuli [2,3]. While a thymus in a healthy animal can be normally recovered from these damages, a relatively prolonged process of the thymic recovery may impair T cell-mediated immunity due to a reduced replenishment of naïve T cell repertoire during the recovery period [3,4].Sub-lethal dose radiation on mice has been utilized as an experimental model of the thymic regeneration after insults [5,6]. Ionizing irradiation is also broadly used for hematopoietic transplantation and cancer therapy [7,8], and total body irradiation causes an acute thymic injury and slow recovery of thymopoiesis. Several studies showed that irradiation reduces cellularity not only of thymocytes but also of thymic epithelial cells (TECs), which are major constituents of the thymic environment [5,9,10]. Because the thymopoiesis is supported by interactions between the thymocytes and the TECs [11], understanding thymic recovery requires a characterization of the reciprocal regulations between the thymocytes and the TECs.Concomitantly, various techniques to trace, perturb, and quantify the cells involved in the events have enabled us to characterize their kinetics and dynamics quantitatively [12][13][14][15]. By combining mathematical models with such quantitative data, dynamic aspects of thymopoiesis have been distilled in the forms of more detailed kinetic information, e.g., rates of proliferation, death, and differentiation [12,16]. Mehr et al.[17] had developed the first kinetic model of the thymocyte development using ordinary differential equations (ODEs) [18]. Since this pioneering work, kinetic models of the thymopoiesis have been progressively refined by taking into account of the detailed cellularity and developmental states of the thy...

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T cell development in the thymus: From periodic seeding to constant output

Cited by 11 publications

References 28 publications

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

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

The Thymic Niche Does Not Limit Development of the Naturally Diverse Population of Mouse Regulatory T Lymphocytes

Quantitative Analysis Reveals Reciprocal Regulations Underlying Recovery Dynamics of Thymocytes and Thymic Environment

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