title: In silico simulations suggest that Th-cell development is regulated by both selective and instructive mechanisms.
abstract: 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.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia. andreas.jansson@his.se
authors.forename: Andreas
authors.initials: A
authors.lastname: Jansson
authors.forename: Magnus
authors.initials: M
authors.lastname: Fagerlind
authors.forename: Diana
authors.initials: D
authors.lastname: Karlsson
authors.forename: Patric
authors.initials: P
authors.lastname: Nilsson
authors.forename: Margaret
authors.initials: M
authors.lastname: Cooley
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35; D015847:Interleukin-4 / Q000378:metabolism*; D018448:Models, Immunological; D021122:Protein Subunits / Q000378:metabolism*; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
chemical_list: C508858:IL12A protein, human; C508598:IL4 protein, human; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D018664:Interleukin-12; D015847:Interleukin-4