title: Diversity and plasticity of Th cell types predicted from regulatory network modelling.
abstract: Alternative cell differentiation pathways are believed to arise from the concerted action of signalling pathways and transcriptional regulatory networks. However, the prediction of mammalian cell differentiation from the knowledge of the presence of specific signals and transcriptional factors is still a daunting challenge. In this respect, the vertebrate hematopoietic system, with its many branching differentiation pathways and cell types, is a compelling case study. In this paper, we propose an integrated, comprehensive model of the regulatory network and signalling pathways controlling Th cell differentiation. As most available data are qualitative, we rely on a logical formalism to perform extensive dynamical analyses. To cope with the size and complexity of the resulting network, we use an original model reduction approach together with a stable state identification algorithm. To assess the effects of heterogeneous environments on Th cell differentiation, we have performed a systematic series of simulations considering various prototypic environments. Consequently, we have identified stable states corresponding to canonical Th1, Th2, Th17 and Treg subtypes, but these were found to coexist with other transient hybrid cell types that co-express combinations of Th1, Th2, Treg and Th17 markers in an environment-dependent fashion. In the process, our logical analysis highlights the nature of these cell types and their relationships with canonical Th subtypes. Finally, our logical model can be used to explore novel differentiation pathways in silico.
authors.affiliation: Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Naldi
authors.forename: Jorge
authors.initials: J
authors.lastname: Carneiro
authors.forename: Claudine
authors.initials: C
authors.lastname: Chaouiya
authors.forename: Denis
authors.initials: D
authors.lastname: Thieffry
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D007378:Interleukins / Q000276:immunology / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D018448:Models, Immunological; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D007378:Interleukins; D014157:Transcription Factors
references.citation: Immunol Rev. 2007 Apr;216:48-68
references.pmid: 17367334
references.citation: Immunol Rev. 2006 Aug;212:8-27
references.pmid: 16903903
references.citation: J Exp Med. 1997 Mar 3;185(5):817-24
references.pmid: 9120387
references.citation: Blood. 2007 Oct 15;110(8):2983-90
references.pmid: 17644734
references.citation: Immunol Lett. 2007 Nov 30;114(1):1-8
references.pmid: 17936914
references.citation: Nature. 2008 May 8;453(7192):236-40
references.pmid: 18368049
references.citation: Biosystems. 2009 Aug;97(2):134-9
references.pmid: 19426782
references.citation: Int Immunol. 1995 Aug;7(8):1265-77
references.pmid: 7495733
references.citation: Cell. 2006 Jul 28;126(2):253-6
references.pmid: 16873058
references.citation: Genes Dev. 2003 Sep 15;17(18):2205-32
references.pmid: 12975316
references.citation: Nat Rev Immunol. 2008 Jul;8(7):523-32
references.pmid: 18566595
references.citation: Nat Immunol. 2008 Dec;9(12):1341-6
references.pmid: 18931678
references.citation: Eur J Immunol. 2008 Sep;38(9):2573-86
references.pmid: 18792410
references.citation: Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
references.pmid: 16911870
references.citation: Science. 2009 Mar 13;323(5920):1488-92
references.pmid: 19286559
references.citation: Eur J Immunol. 2009 Apr;39(4):948-55
references.pmid: 19291701
references.citation: Nature. 2009 Mar 19;458(7236):351-6
references.pmid: 19182775
references.citation: Immunity. 2010 Jan 29;32(1):116-28
references.pmid: 20079668
references.citation: Science. 2003 Feb 14;299(5609):1057-61
references.pmid: 12522256
references.citation: Immunity. 2009 Sep 18;31(3):450-2
references.pmid: 19766087
references.citation: Nat Immunol. 2005 Nov;6(11):1133-41
references.pmid: 16200068
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
references.pmid: 16698929
references.citation: J Theor Biol. 2000 Nov 21;207(2):231-54
references.pmid: 11034831
references.citation: Nat Immunol. 2007 Sep;8(9):967-74
references.pmid: 17581537
references.citation: Int Immunol. 2008 Oct;20(10):1269-77
references.pmid: 18765426
references.citation: J Immunol. 2009 Sep 15;183(6):3731-41
references.pmid: 19710455
references.citation: Immunity. 2002 Dec;17(6):703-12
references.pmid: 12479817
references.citation: PLoS Comput Biol. 2007 Aug;3(8):e163
references.pmid: 17722974
references.citation: J Immunol. 1986 Apr 1;136(7):2348-57
references.pmid: 2419430
references.citation: J Theor Biol. 1998 Jan 21;190(2):161-78
references.pmid: 9538464
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1903-8
references.pmid: 19174509
references.citation: J Immunol. 2005 Feb 15;174(4):2071-83
references.pmid: 15699137
references.citation: Nat Immunol. 2007 Dec;8(12):1390-7
references.pmid: 17994024
references.citation: Biosystems. 2006 May;84(2):101-14
references.pmid: 16386358
references.citation: Nat Immunol. 2008 Dec;9(12):1347-55
references.pmid: 18997793
references.citation: Annu Rev Immunol. 2003;21:305-34
references.pmid: 12471050
references.citation: Nat Immunol. 2008 Feb;9(2):194-202
references.pmid: 18157133
references.citation: J Immunol. 2007 Jun 1;178(11):6725-9
references.pmid: 17513718
references.citation: Semin Immunol. 2007 Dec;19(6):409-17
references.pmid: 18053739
references.citation: PLoS Biol. 2007 Feb;5(2):e38
references.pmid: 17298177
references.citation: Annu Rev Immunol. 2007;25:821-52
references.pmid: 17201677
references.citation: J Exp Med. 2005 Nov 7;202(9):1289-300
references.pmid: 16275766
references.citation: Immunity. 1999 Feb;10(2):249-59
references.pmid: 10072077
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4793-8
references.pmid: 19273860
references.citation: Immunity. 2009 May;30(5):721-30
references.pmid: 19427242
references.citation: J Theor Biol. 1994 Sep 7;170(1):25-56
references.pmid: 7967633
references.citation: Bull Math Biol. 1995 Mar;57(2):247-76
references.pmid: 7703920
references.citation: Nat Immunol. 2008 Jun;9(6):641-9
references.pmid: 18454151
references.citation: Nat Immunol. 2008 Jan;9(1):34-41
references.pmid: 18059273
references.citation: Immunity. 1998 Aug;9(2):229-37
references.pmid: 9729043
references.citation: Nat Immunol. 2009 Jun;10(6):595-602
references.pmid: 19412181
references.citation: J Biol Chem. 2004 Nov 5;279(45):46818-25
references.pmid: 15319439
references.citation: J Exp Med. 2007 Jan 22;204(1):65-71
references.pmid: 17227909
references.citation: J Exp Med. 2008 Sep 1;205(9):1983-91
references.pmid: 18725525
references.citation: J Exp Med. 1999 Nov 15;190(10):1439-50
references.pmid: 10562319
references.citation: Bioinformatics. 2006 Jul 15;22(14):e124-31
references.pmid: 16873462
references.citation: Mol Immunol. 2008 Jun;45(11):3205-12
references.pmid: 18395799
references.citation: Nat Immunol. 2007 Feb;8(2):145-53
references.pmid: 17195845
references.citation: J Exp Med. 2009 Jul 6;206(7):1549-64
references.pmid: 19546248
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9364-8
references.pmid: 12087127
references.citation: Annu Rev Immunol. 1989;7:145-73
references.pmid: 2523712
references.citation: Brief Bioinform. 2007 Jul;8(4):220-5
references.pmid: 17626067
references.citation: Immunity. 2007 Mar;26(3):371-81
references.pmid: 17363300
references.citation: Theor Biol Med Model. 2006 Mar 16;3:13
references.pmid: 16542429
references.citation: J Theor Biol. 1987 Nov 21;129(2):141-62
references.pmid: 2458507
references.citation: Bull Math Biol. 2001 May;63(3):405-30
references.pmid: 11374299
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43
references.pmid: 15790681
references.citation: J Immunol. 2004 Sep 15;173(6):3871-7
references.pmid: 15356135
references.citation: Blood. 2007 May 15;109(10):4368-75
references.pmid: 17227828
references.citation: J Neuroimmunol. 2009 Oct 30;215(1-2):10-24
references.pmid: 19692128
references.citation: Nat Immunol. 2008 Jun;9(6):632-40
references.pmid: 18438410
references.citation: Cell. 2006 Sep 22;126(6):1121-33
references.pmid: 16990136
references.citation: Eur J Immunol. 2008 Dec;38(12):3274-81
references.pmid: 19039774
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070
references.citation: Genes Dev. 2000 Jul 15;14(14):1693-711
references.pmid: 10898785