Diversity and plasticity of Th cell types predicted from regulatory network modelling.
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.
Naldi
Aurélien
A
Technological Advances for Genomics and Clinics, INSERM U928, Marseille, France.
Carneiro
Jorge
J
Chaouiya
Claudine
C
Thieffry
Denis
D
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
D007378:Interleukins; D014157:Transcription Factors
Immunol Rev. 2007 Apr;216:48-68
17367334
Immunol Rev. 2006 Aug;212:8-27
16903903
J Exp Med. 1997 Mar 3;185(5):817-24
9120387
Blood. 2007 Oct 15;110(8):2983-90
17644734
Immunol Lett. 2007 Nov 30;114(1):1-8
17936914
Nature. 2008 May 8;453(7192):236-40
18368049
Biosystems. 2009 Aug;97(2):134-9
19426782
Int Immunol. 1995 Aug;7(8):1265-77
7495733
Cell. 2006 Jul 28;126(2):253-6
16873058
Genes Dev. 2003 Sep 15;17(18):2205-32
12975316
Nat Rev Immunol. 2008 Jul;8(7):523-32
18566595
Nat Immunol. 2008 Dec;9(12):1341-6
18931678
Eur J Immunol. 2008 Sep;38(9):2573-86
18792410
Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
16911870
Science. 2009 Mar 13;323(5920):1488-92
19286559
Eur J Immunol. 2009 Apr;39(4):948-55
19291701
Nature. 2009 Mar 19;458(7236):351-6
19182775
Immunity. 2010 Jan 29;32(1):116-28
20079668
Science. 2003 Feb 14;299(5609):1057-61
12522256
Immunity. 2009 Sep 18;31(3):450-2
19766087
Nat Immunol. 2005 Nov;6(11):1133-41
16200068
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
16698929
J Theor Biol. 2000 Nov 21;207(2):231-54
11034831
Nat Immunol. 2007 Sep;8(9):967-74
17581537
Int Immunol. 2008 Oct;20(10):1269-77
18765426
J Immunol. 2009 Sep 15;183(6):3731-41
19710455
Immunity. 2002 Dec;17(6):703-12
12479817
PLoS Comput Biol. 2007 Aug;3(8):e163
17722974
J Immunol. 1986 Apr 1;136(7):2348-57
2419430
J Theor Biol. 1998 Jan 21;190(2):161-78
9538464
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1903-8
19174509
J Immunol. 2005 Feb 15;174(4):2071-83
15699137
Nat Immunol. 2007 Dec;8(12):1390-7
17994024
Biosystems. 2006 May;84(2):101-14
16386358
Nat Immunol. 2008 Dec;9(12):1347-55
18997793
Annu Rev Immunol. 2003;21:305-34
12471050
Nat Immunol. 2008 Feb;9(2):194-202
18157133
J Immunol. 2007 Jun 1;178(11):6725-9
17513718
Semin Immunol. 2007 Dec;19(6):409-17
18053739
PLoS Biol. 2007 Feb;5(2):e38
17298177
Annu Rev Immunol. 2007;25:821-52
17201677
J Exp Med. 2005 Nov 7;202(9):1289-300
16275766
Immunity. 1999 Feb;10(2):249-59
10072077
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4793-8
19273860
Immunity. 2009 May;30(5):721-30
19427242
J Theor Biol. 1994 Sep 7;170(1):25-56
7967633
Bull Math Biol. 1995 Mar;57(2):247-76
7703920
Nat Immunol. 2008 Jun;9(6):641-9
18454151
Nat Immunol. 2008 Jan;9(1):34-41
18059273
Immunity. 1998 Aug;9(2):229-37
9729043
Nat Immunol. 2009 Jun;10(6):595-602
19412181
J Biol Chem. 2004 Nov 5;279(45):46818-25
15319439
J Exp Med. 2007 Jan 22;204(1):65-71
17227909
J Exp Med. 2008 Sep 1;205(9):1983-91
18725525
J Exp Med. 1999 Nov 15;190(10):1439-50
10562319
Bioinformatics. 2006 Jul 15;22(14):e124-31
16873462
Mol Immunol. 2008 Jun;45(11):3205-12
18395799
Nat Immunol. 2007 Feb;8(2):145-53
17195845
J Exp Med. 2009 Jul 6;206(7):1549-64
19546248
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9364-8
12087127
Annu Rev Immunol. 1989;7:145-73
2523712
Brief Bioinform. 2007 Jul;8(4):220-5
17626067
Immunity. 2007 Mar;26(3):371-81
17363300
Theor Biol Med Model. 2006 Mar 16;3:13
16542429
J Theor Biol. 1987 Nov 21;129(2):141-62
2458507
Bull Math Biol. 2001 May;63(3):405-30
11374299
Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43
15790681
J Immunol. 2004 Sep 15;173(6):3871-7
15356135
Blood. 2007 May 15;109(10):4368-75
17227828
J Neuroimmunol. 2009 Oct 30;215(1-2):10-24
19692128
Nat Immunol. 2008 Jun;9(6):632-40
18438410
Cell. 2006 Sep 22;126(6):1121-33
16990136
Eur J Immunol. 2008 Dec;38(12):3274-81
19039774
Nat Immunol. 2005 Nov;6(11):1123-32
16200070
Genes Dev. 2000 Jul 15;14(14):1693-711
10898785