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  • 1.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Fagerlind, Magnus
    University of Skövde, School of Life Sciences.
    Karlsson, Diana
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
    In silico simulations suggest that Th-cell development is regulated by both selective and instructive mechanisms2006In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 84, no 2, p. 218-226Article in journal (Refereed)
    Abstract [en]

    Th-cell differentiation is highly influenced by the local cytokine environment. Although cytokines such as IL-12 and IL-4 are known to polarize the Th-cell response towards Th1 or Th2, respectively, it is not known whether these cytokines instruct the developmental fate of uncommitted Th cells or select cells that have already been committed through a stochastic process. We present an individual based model that accommodates both stochastic and deterministic processes to simulate the dynamic behaviour of selective versus instructive Th-cell development. The predictions made by each model show distinct behaviours, which are compared with experimental observations. The simulations show that the instructive model generates an exclusive Th1 or Th2 response in the absence of an external cytokine source, whereas the selective model favours coexistence of the phenotypes. A hybrid model, including both instructive and selective development, shows behaviour similar to either the selective or the instructive model dependent on the strength of activation. The hybrid model shows the closest qualitative agreement with a number of well-established experimental observations. The predictions by each model suggest that neither pure selective nor instructive Th development is likely to be functional as exclusive mechanisms in Th1/Th2 development.

  • 2.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2033, Australia.
    3D computation modelling of the influence of cytokine secretion on Th-cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL-4 for Th2 cell dominance2007In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 85, no 3, p. 189-196Article in journal (Refereed)
    Abstract [en]

    Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (IFN-italic gamma) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor–ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 mum and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

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