dc.contributor.author	Hong, Tian	en
dc.contributor.author	Xing, Jianhua	en
dc.contributor.author	Li, Liwu	en
dc.contributor.author	Tyson, John J.	en
dc.contributor.department	Biological Sciences	en
dc.contributor.department	Fralin Life Sciences Institute	en
dc.date.accessioned	2016-12-09T21:37:12Z	en
dc.date.available	2016-12-09T21:37:12Z	en
dc.date.issued	2012-06-14	en
dc.description.abstract	Background CD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Therefore, conceptual understanding of induced heterogeneous differentiation will shed light on the mechanisms controlling the response of populations of CD4+ T cells under physiological conditions. Results We present a simple theoretical framework to show how heterogeneous differentiation in a two-master-regulator paradigm can be governed by a signaling network motif common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. We provide three prototype models illustrating how to use this framework to explain experimental observations and make specific testable predictions. Conclusions The process in which several types of T helper cells are generated simultaneously to mount complex immune responses upon pathogenic challenges can be highly regulated, and a simple signaling network motif can be responsible for generating all possible types of heterogeneous populations with respect to a pair of master regulators controlling CD4+ T cell differentiation. The framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cells, and it can be helpful for interpreting experimental results. Mathematical models based on the framework make specific testable predictions that may improve our understanding of this differentiation system.	en
dc.description.version	Published version	en
dc.format.extent	? - ? (17) page(s)	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	BMC Systems Biology. 2012 Jun 14;6(1):66	en
dc.identifier.doi	https://doi.org/10.1186/1752-0509-6-66	en
dc.identifier.issn	1752-0509	en
dc.identifier.uri	http://hdl.handle.net/10919/73637	en
dc.identifier.volume	6	en
dc.language.iso	en	en
dc.publisher	Biomed Central	en
dc.relation.uri	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000308706100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1	en
dc.rights	Creative Commons Attribution 4.0 International	en
dc.rights.holder	Tian Hong et al.; licensee BioMed Central Ltd.	en
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	en
dc.subject	Mathematical & Computational Biology	en
dc.subject	ROR-GAMMA-T	en
dc.subject	T(H)17 CELLS	en
dc.subject	TGF-BETA	en
dc.subject	TH2 DIFFERENTIATION	en
dc.subject	LINEAGE-COMMITMENT	en
dc.subject	PROGENITOR CELLS	en
dc.subject	RETINOIC ACID	en
dc.subject	GENE	en
dc.subject	CYTOKINE	en
dc.subject	GATA-3	en
dc.title	A simple theoretical framework for understanding heterogeneous differentiation of CD4(+) T cells	en
dc.title.serial	BMC Systems Biology	en
dc.type	Article - Refereed	en
dc.type.dcmitype	Text	en
pubs.organisational-group	/Virginia Tech	en
pubs.organisational-group	/Virginia Tech/All T&R Faculty	en
pubs.organisational-group	/Virginia Tech/Faculty of Health Sciences	en
pubs.organisational-group	/Virginia Tech/Science	en
pubs.organisational-group	/Virginia Tech/Science/Biological Sciences	en
pubs.organisational-group	/Virginia Tech/Science/COS T&R Faculty	en
pubs.organisational-group	/Virginia Tech/University Distinguished Professors	en

A simple theoretical framework for understanding heterogeneous differentiation of CD4(+) T cells

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