Tracking Proliferative History in Lymphocyte Development with Cre-Mediated Sister Chromatid Recombination

Zhang, Baojun; Dai, Meifang; Li, Qi-Jing; Zhuang, Yuan

doi:10.1371/journal.pgen.1003887

Cited by 6 publications

(11 citation statements)

References 34 publications

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“…Because the Vγ1.1/Vδ6.3 subset develops and expands perinatally (Zhang, Dai et al 2013), we sought to determine the dynamics of IL-13 production throughout the life of Id3 knockout mice. By examining neonatal mice (6 days old), we were able to determine whether T cells gain IL-13 competency in the thymus early in life, prior to recirculation of peripherally derived effector T cells.…”

Section: : Resultsmentioning

confidence: 99%

Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice

et al. 2014

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Elevated levels of the cytokine IL-13 has been found to be associated with autoimmune diseases, including Sjögren’s Syndrome. However, whether IL-13 plays a causative role in disease development is not known and cannot be easily studied in humans. Our previous work has shown that levels of IL-13 are elevated in Id3 knockout mice, which has been established as a model for primary Sjögren’s Syndrome. Here, we utilized an IL-13 reporter to determine the source of the elevated IL-13 levels observed in Id3 knockout mice and assess its contribution to SS pathology. Our results indicate that T cells, notably CD4 and γδ T cells, in Id3 knockout mice acquire IL-13 competency at an elevated rate well before disease symptoms become apparent. We also show that T cells developing early in life are more predisposed to produce IL-13. Finally, analysis of Id3 and IL-13 double deficient mice demonstrated that IL-13 plays an essential role in the deterioration of gland function. Our study provides crucial genetic evidence that enhanced IL-13 production by T cells can play a causative role in the exocrinopathy observed in Id3 knockout mice.

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Section: : Resultsmentioning

confidence: 99%

Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice

et al. 2014

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“…Our previous studies have demonstrated that the Tlox system could be used to track lymphocyte proliferation in combination with appropriate Cre transgenes (25). Cre-mediated recombination between a paired Tlox sites on sister chromatids occurs exclusively during cell cycle, resulting in permanent activation of the tdTomato marker from the Tlox reporter among a fraction of the daughter cells ( Figure 1A).…”

Section: Tlox/ox40cre System Tracks a Population Of Post Expansion Tregsmentioning

confidence: 99%

“…(2) tdTomato positive cells come from tdTomato negative cells but not vice versa. 3Because the labeling frequency cannot be higher than 25% per cell cycle (25), both tdTomato positive and negative cells can be generated from the non-labeled founder cells. (4) Assuming Cre activity remains stable during clonal expansion, the frequency of non-labeled descendants reduces after each cell cycle, as such tdTomato labeled fractions will become the dominant population within the expanded clones.…”

Section: Supplementalmentioning

confidence: 99%

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Lineage Tracking the Generation of T Regulatory Cells From Microbial Activated T Effector Cells in Naïve Mice

Zhu

Liu

et al. 2020

Front. Immunol.

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Regulatory T cells (Tregs) are essential for the maintenance of gut homeostasis by suppressing conventional CD4 + helper T cells (Tconvs) that are activated by microbial antigens. Although thymus is the major source of the peripheral Tregs, peripheral conversion from Tconvs to Tregs have also been shown to occur under various experimental conditions. It remains less clear about the frequency of lineage conversion from Tconvs to Tregs in naïve animals. Here we used a newly established reporter system to track a group of post expansion Tregs (eTregs), which exhibited a stronger suppressive ability than the non-lineage marked Tregs. Notably, microbial antigens are the primary driver for the formation of eTregs. TCR repertoire analysis of Peyer's patch T cells revealed that eTregs are clonally related to Tconvs, but not to the non-lineage tracked Tregs. Adoptive transfer of Tconvs into lymphopenic hosts demonstrated a conversion from Tconvs to eTregs. Thus, our lineage tracking method was able to capture the lineage conversion from microbial activated effector T cells to Tregs in naïve animals. This study suggests that a fraction of clonally activated T cells from the natural T cell repertoire exhibits lineage conversion to Tregs in response to commensal microbes under homeostatic conditions.

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“…Example 3: the offspring of a label-positive cell experience asymmetric label-loss. There are genetic constructs where, on division, labels are lost asymmetrically [73]. That is, if a label-positive cell divides in two and one of its two offspring loses its label, then the other does not.…”

Section: Assumptionmentioning

confidence: 99%

Inferring average generation via division-linked labeling

2016

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For proliferating cells subject to both division and death, how can one estimate the average generation number of the living population without continuous observation or a division-diluting dye? In this paper we provide a method for cell systems such that at each division there is an unlikely, heritable one-way label change that has no impact other than to serve as a distinguishing marker. If the probability of label change per cell generation can be determined and the proportion of labeled cells at a given time point can be measured, we establish that the average generation number of living cells can be estimated. Crucially, the estimator does not depend on knowledge of the statistics of cell cycle, death rates or total cell numbers. We validate the estimator and illustrate its features through comparison with published data and physiologically parameterized stochastic simulations, using it to suggest new experimental designs.

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Tracking Proliferative History in Lymphocyte Development with Cre-Mediated Sister Chromatid Recombination

Cited by 6 publications

References 34 publications

Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice

Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice

Lineage Tracking the Generation of T Regulatory Cells From Microbial Activated T Effector Cells in Naïve Mice

Inferring average generation via division-linked labeling

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