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Stochastic Cytokine Expression Induces Mixed T Helper Cell States

During eukaryotic development, the induction of a lineage-specific transcription factor typically drives differentiation of multipotent progenitor cells, while repressing that of alternative lineages. This process is often mediated by some extracellular signaling molecules, such as cytokines that ca...

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Autores principales: Fang, Miaoqing, Xie, Huangming, Dougan, Stephanie K., Ploegh, Hidde, van Oudenaarden, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728019/
https://www.ncbi.nlm.nih.gov/pubmed/23935453
http://dx.doi.org/10.1371/journal.pbio.1001618
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author Fang, Miaoqing
Xie, Huangming
Dougan, Stephanie K.
Ploegh, Hidde
van Oudenaarden, Alexander
author_facet Fang, Miaoqing
Xie, Huangming
Dougan, Stephanie K.
Ploegh, Hidde
van Oudenaarden, Alexander
author_sort Fang, Miaoqing
collection PubMed
description During eukaryotic development, the induction of a lineage-specific transcription factor typically drives differentiation of multipotent progenitor cells, while repressing that of alternative lineages. This process is often mediated by some extracellular signaling molecules, such as cytokines that can bind to cell surface receptors, leading to activation and/or repression of transcription factors. We explored the early differentiation of naive CD4 T helper (Th) cells into Th1 versus Th2 states by counting single transcripts and quantifying immunofluorescence in individual cells. Contrary to mutually exclusive expression of antagonistic transcription factors, we observed their ubiquitous co-expression in individual cells at high levels that are distinct from basal-level co-expression during lineage priming. We observed that cytokines are expressed only in a small subpopulation of cells, independent from the expression of transcription factors in these single cells. This cell-to-cell variation in the cytokine expression during the early phase of T helper cell differentiation is significantly larger than in the fully differentiated state. Upon inhibition of cytokine signaling, we observed the classic mutual exclusion of antagonistic transcription factors, thus revealing a weak intracellular network otherwise overruled by the strong signals that emanate from extracellular cytokines. These results suggest that during the early differentiation process CD4 T cells acquire a mixed Th1/Th2 state, instructed by extracellular cytokines. The interplay between extracellular and intracellular signaling components unveiled in Th1/Th2 differentiation may be a common strategy for mammalian cells to buffer against noisy cytokine expression.
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spelling pubmed-37280192013-08-09 Stochastic Cytokine Expression Induces Mixed T Helper Cell States Fang, Miaoqing Xie, Huangming Dougan, Stephanie K. Ploegh, Hidde van Oudenaarden, Alexander PLoS Biol Research Article During eukaryotic development, the induction of a lineage-specific transcription factor typically drives differentiation of multipotent progenitor cells, while repressing that of alternative lineages. This process is often mediated by some extracellular signaling molecules, such as cytokines that can bind to cell surface receptors, leading to activation and/or repression of transcription factors. We explored the early differentiation of naive CD4 T helper (Th) cells into Th1 versus Th2 states by counting single transcripts and quantifying immunofluorescence in individual cells. Contrary to mutually exclusive expression of antagonistic transcription factors, we observed their ubiquitous co-expression in individual cells at high levels that are distinct from basal-level co-expression during lineage priming. We observed that cytokines are expressed only in a small subpopulation of cells, independent from the expression of transcription factors in these single cells. This cell-to-cell variation in the cytokine expression during the early phase of T helper cell differentiation is significantly larger than in the fully differentiated state. Upon inhibition of cytokine signaling, we observed the classic mutual exclusion of antagonistic transcription factors, thus revealing a weak intracellular network otherwise overruled by the strong signals that emanate from extracellular cytokines. These results suggest that during the early differentiation process CD4 T cells acquire a mixed Th1/Th2 state, instructed by extracellular cytokines. The interplay between extracellular and intracellular signaling components unveiled in Th1/Th2 differentiation may be a common strategy for mammalian cells to buffer against noisy cytokine expression. Public Library of Science 2013-07-30 /pmc/articles/PMC3728019/ /pubmed/23935453 http://dx.doi.org/10.1371/journal.pbio.1001618 Text en © 2013 Fang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fang, Miaoqing
Xie, Huangming
Dougan, Stephanie K.
Ploegh, Hidde
van Oudenaarden, Alexander
Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title_full Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title_fullStr Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title_full_unstemmed Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title_short Stochastic Cytokine Expression Induces Mixed T Helper Cell States
title_sort stochastic cytokine expression induces mixed t helper cell states
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728019/
https://www.ncbi.nlm.nih.gov/pubmed/23935453
http://dx.doi.org/10.1371/journal.pbio.1001618
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