Dataset Information

Stochastic Inheritance of Division and Death Times Determines the Size and Phenotype of CD8+ T Cell Families.

ABSTRACT: After antigen stimulation cognate naïve CD8+ T cells undergo rapid proliferation and ultimately their progeny differentiates into short-lived effectors and longer-lived memory T cells. Although the expansion of individual cells is very heterogeneous, the kinetics are reproducible at the level of the total population of cognate cells. After the expansion phase, the population contracts, and if antigen is cleared, a population of memory T cells remains behind. Different markers like CD62L, CD27, and KLRG1 have been used to define several T cell subsets (or cell fates) developing from individual naïve CD8+ T cells during the expansion phase. Growing evidence from high-throughput experiments, like single cell RNA sequencing, epigenetic profiling, and lineage tracing, highlights the need to model this differentiation process at the level of single cells. We model CD8+ T cell proliferation and differentiation as a competitive process between the division and death probabilities of individual cells (like in the Cyton model). We use an extended form of the Cyton model in which daughter cells inherit the division and death times from their mother cell in a stochastic manner (using lognormal distributions). We show that this stochastic model reproduces the dynamics of CD8+ T cells both at the population and at the single cell level. Modeling the expression of the CD62L, CD27, and KLRG1 markers of each individual cell, we find agreement with the changing phenotypic distributions of these markers in single cell RNA sequencing data. Retrospectively re-defining conventional T-cell subsets by "gating" on these markers, we find agreement with published population data, without having to assume that these subsets have different properties, i.e., correspond to different fates.

SUBMITTER: Pandit A

PROVIDER: S-EPMC6426761 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Stochastic Inheritance of Division and Death Times Determines the Size and Phenotype of CD8<sup>+</sup> T Cell Families.

Pandit Aridaman A De Boer Rob J RJ

Frontiers in immunology 20190314

After antigen stimulation cognate naïve CD8<sup>+</sup> T cells undergo rapid proliferation and ultimately their progeny differentiates into short-lived effectors and longer-lived memory T cells. Although the expansion of individual cells is very heterogeneous, the kinetics are reproducible at the level of the total population of cognate cells. After the expansion phase, the population contracts, and if antigen is cleared, a population of memory T cells remains behind. Different markers like CD6 ...[more]

PMID: 30923522

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Project description:CD4+ and CD8+ effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4+ T cells, including IL-17+ CD4+ T cells. Here, we further characterized the regulation of IL-10 expression via blockade of TNF signaling or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4+ T cell/monocyte cocultures led to increased percentages of IL-10+ cells in pro-inflammatory IL-17+, IFNγ+, TNFα+, GM-CSF+, and IL-4+ CD4+ T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10+ cell frequencies. TNF blockade also regulated IL-10 expression in CD4+ T cells upon antigenic stimulation. Using time course experiments in whole peripheral blood mononuclear cell (PBMC) cultures, we show that TNF blockade maintained, rather than increased, IL-10+ cell frequencies in both CD4+ and CD8+ T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4+ or CD8+ T cell subpopulations. We show that TNF blockade acts directly on effector CD4+ T cells, in the absence of monocytes or CD4+ CD25highCD127low regulatory T cells and independently of IL-27, resulting in higher IL-10+ frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10+ CD4+ T cell frequencies in 3-day CD4+ T cell/monocyte cocultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together, these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10+ phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy.

Dataset Information

Stochastic Inheritance of Division and Death Times Determines the Size and Phenotype of CD8+ T Cell Families.

Publications

Stochastic Inheritance of Division and Death Times Determines the Size and Phenotype of CD8<sup>+</sup> T Cell Families.

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