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A robust model to describe the differentiation of T-helper cells

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Abstract

There is a wealth of information regarding the differentiation of T-helper cells. Nevertheless, there is no general agreement on the topology and dynamical properties of the molecular network controlling the differentiation of these cells. This paper presents a continuous dynamical system to model the signaling network that controls the differentiation process of T-helper cells. The model is able to represent the differentiation from the precursor Th0 cell to any of the four effectors types (Th1, Th2, Th17, and Treg), as well as the phenotype of single null mutants. We present the first sensitivity analysis of the equations defining the Th model, showing that the qualitative dynamical behavior of the model is very robust against changes in three out of four tested parameters. The robustness of the model is in agreement with our claim that the qualitative behavior of the system is to a large extent independent of the methodological framework used for modeling.

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References

  • Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8:639–646

    Article  CAS  PubMed  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441:235–238

    Article  CAS  PubMed  Google Scholar 

  • Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, Höfer T (2010) Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci USA 107:3058–3063

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 198:1875–1886

    Article  CAS  PubMed  Google Scholar 

  • Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-β induces a regulatory phenotype in CD4 + CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153

    CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory cells. Nat Immunol 4:30–336

    Article  Google Scholar 

  • Garg A, Xenarios I, Mendoza L, De Micheli G (2007) Efficient methods for dynamic analysis of genetic networks and in silico gene perturbation experiments. Lect Notes Comput Sci 4453:62–76

    Article  Google Scholar 

  • Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445:771–775

    Article  CAS  PubMed  Google Scholar 

  • Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  CAS  PubMed  Google Scholar 

  • Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    CAS  PubMed  Google Scholar 

  • Höfer T, Nathansen H, Löhning M, Radbruch A, Heinrich R (2002) GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model. Proc Natl Acad Sci USA 99:9364–9368

    Article  PubMed  Google Scholar 

  • Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17 + T helper cells. Cell 126:1121–1133

    Article  CAS  PubMed  Google Scholar 

  • Iwakura Y, Ishigame H (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218–1222

    Article  CAS  PubMed  Google Scholar 

  • Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 17:233–240

    Article  Google Scholar 

  • Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    Article  CAS  PubMed  Google Scholar 

  • Mendoza L (2006) A network model for the control of the differentiation process in Th cells. BioSystems 84:101–114

    Article  CAS  PubMed  Google Scholar 

  • Mendoza L, Xenarios I (2006) A method for the generation of standardized qualitative dynamical systems of regulatory networks. Theor Biol Med Model 3:13

    Article  PubMed  Google Scholar 

  • Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh K, Vega F, To W, Wagner J, O’Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein DA, de Waal Malefyt R, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R1. J Immunol 168:5699–5708

    CAS  PubMed  Google Scholar 

  • Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  CAS  PubMed  Google Scholar 

  • Reiner SL (2005) Epigenetic control in the immune response. Hum Mol Genet 14:R41–R46

    Article  CAS  PubMed  Google Scholar 

  • Reiner SL (2007) Development in motion: helper T cells at work. Cell 129:33–36

    Article  CAS  PubMed  Google Scholar 

  • Remy E, Ruet P, Mendoza L, Thieffry D, Chaouiya C (2006) From logical regulatory graphs to standard petri nets: dynamical roles and functionality of feedback circuits. Lect Notes Comput Sci 4230:56–72

    Article  Google Scholar 

  • Sánchez-Corrales YE, Alvarez-Buylla ER, Mendoza L (2010) The Arabidopsis thaliana flower organ specification gene regulatory network determines a robust differentiation process. J Theor Biol 264:971–983

    Article  PubMed  Google Scholar 

  • Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM (2006) The lifestyle of naturally occurring CD4 + CD25 + Foxp3 + regulatory T cells. Immunol Rev 212:60–73

    Article  CAS  PubMed  Google Scholar 

  • Steinman L (2007) A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145

    Article  CAS  PubMed  Google Scholar 

  • Tato CM, O’Shea JJ (2006) What does it mean to be just 17? Nature 441:166–168

    Article  CAS  PubMed  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  CAS  PubMed  Google Scholar 

  • Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445:766–770

    Article  CAS  PubMed  Google Scholar 

  • Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688

    Article  CAS  PubMed  Google Scholar 

  • Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284

    Article  CAS  PubMed  Google Scholar 

  • Wilson CB, Makar KW, Shnyreva M, Fitzpatrick DR (2005) DNA methylation and the expanding epigenetics of T cell lineage commitment. Semin Immunol 17:105–119

    Article  CAS  PubMed  Google Scholar 

  • Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, Maeda M, Onodera M, Uchiyama T, Fujii S, Sakaguchi S (2004) Crucial role of FOXP3 in the development and function of human CD25 + CD4 + regulatory T cells. Int Immunol 16:1643–1656

    Article  CAS  PubMed  Google Scholar 

  • Zhong X, Gao W, Degauque N, Bai C, Lu Y, Kenny J, Oukka M, Strom TB, Rothstein TL (2007) Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells. Eur J Immunol 37:2400–2404

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Lopes JE, Chong MMW, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453:236–240

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Authors want to thank two anonymous reviewers, whose suggestions were very valuable to make this manuscript suitable for publication. This work was supported in part by the CONACYT Grant APOY-COMPL-2008 No. 89664 to LM.

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Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico, Mexico

    Luis Mendoza & Fátima Pardo

  2. Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico, Mexico

    Luis Mendoza

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  1. Luis Mendoza
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  2. Fátima Pardo
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Correspondence to Luis Mendoza.

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Mendoza, L., Pardo, F. A robust model to describe the differentiation of T-helper cells. Theory Biosci. 129, 283–293 (2010). https://doi.org/10.1007/s12064-010-0112-x

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  • DOI: https://doi.org/10.1007/s12064-010-0112-x

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