Dataset Information

Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus.

ABSTRACT: T cell antigen receptor (TCR) signaling in the thymus initiates positive selection, but the CD8+-lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We have identified four cytokines (IL-6, IFN-?, TSLP and TGF-?) that did not signal via the common ?-chain (?c) receptor but that, like IL-7 and IL-15, induced expression of the lineage-specifying transcription factor Runx3d and signaled the generation of CD8+ T cells. Elimination of in vivo signaling by all six of these 'lineage-specifying cytokines' during positive selection eliminated Runx3d expression and completely abolished the generation of CD8+ single-positive thymocytes. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8+-lineage-fate 'decisions' in the thymus.

SUBMITTER: Etzensperger R

PROVIDER: S-EPMC5659273 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus.

Etzensperger Ruth R Kadakia Tejas T Tai Xuguang X Alag Amala A Guinter Terry I TI Egawa Takeshi T Erman Batu B Singer Alfred A

Nature immunology 20170925 11

T cell antigen receptor (TCR) signaling in the thymus initiates positive selection, but the CD8+-lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We have identified four cytokines (IL-6, IFN-γ, TSLP and TGF-β) that did not signal via the common γ-chain (γc) receptor but that, like IL-7 and IL-15, induced expression of the lineage-specifying transcription factor Runx3d and signaled the genera ...[more]

PMID: 28945245

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Project description:Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, and to what extent gene expression configures multiple trajectories into commitment. Importantly, the transient nature of the commitment transition confounds the experimental capture of committing cells. We develop a computational framework that simulates stochastic commitment events, and affords mechanistic exploration of the fate transition. We use a combined modeling approach guided by gene expression classifier methods that infers a time-series of stochastic commitment events from experimental growth characteristics and gene expression profiling of individual hematopoietic cells captured immediately before and after commitment. We define putative regulators of commitment and probabilistic rules of transition through machine learning methods, and employ clustering and correlation analyses to interrogate gene regulatory interactions in multipotent cells. Against this background, we develop a Monte Carlo time-series stochastic model of transcription where the parameters governing promoter status, mRNA production and mRNA decay in multipotent cells are fitted to experimental static gene expression distributions. Monte Carlo time is converted to physical time using cell culture kinetic data. Probability of commitment in time is a function of gene expression as defined by a logistic regression model obtained from experimental single-cell expression data. Our approach should be applicable to similar differentiating systems where single cell data is available. Within our system, we identify robust model solutions for the multipotent population within physiologically reasonable values and explore model predictions with regard to molecular scenarios of entry into commitment. The model suggests distinct dependencies of different commitment-associated genes on mRNA dynamics and promoter activity, which globally influence the probability of lineage commitment.

Dataset Information

Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus.

Publications

Identification of lineage-specifying cytokines that signal all CD8<sup>+</sup>-cytotoxic-lineage-fate 'decisions' in the thymus.

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