Hybrid approach to model the spatial regulation of T cell responses

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  • dc.contributor.author Bouchnita, Anassca
  • dc.contributor.author Bocharov, Gennady A.ca
  • dc.contributor.author Meyerhans, Andreasca
  • dc.contributor.author Volpert, Vitalyca
  • dc.date.accessioned 2017-10-23T15:27:04Z
  • dc.date.available 2017-10-23T15:27:04Z
  • dc.date.issued 2017
  • dc.description.abstract BACKGROUND: Moving from the molecular and cellular level to a multi-scale systems understanding of immune responses requires the development of novel approaches to integrate knowledge and data from different biological levels into mechanism-based integrative mathematical models. The aim of our study is to present a methodology for a hybrid modelling of immunological processes in their spatial context. METHODS: A two-level hybrid mathematical model of immune cell migration and interaction integrating cellular and organ levels of regulation for a 2D spatial consideration of idealized secondary lymphoid organs is developed. It considers the population dynamics of antigen-presenting cells, CD4 + and CD8 + T lymphocytes in naive-, proliferation- and differentiated states. Cell division is assumed to be asymmetric and regulated by the extracellular concentration of interleukin-2 (IL-2) and type I interferon (IFN), together controlling the balance between proliferation and differentiation. The cytokine dynamics is described by reaction-diffusion PDEs whereas the intracellular regulation is modelled with a system of ODEs. RESULTS: The mathematical model has been developed, calibrated and numerically implemented to study various scenarios in the regulation of T cell immune responses to infection, in particular the change in the diffusion coefficient of type I IFN as compared to IL-2. We have shown that a hybrid modelling approach provides an efficient tool to describe and analyze the interplay between spatio-temporal processes in the emergence of abnormal immune response dynamics. DISCUSSION: Virus persistence in humans is often associated with an exhaustion of T lymphocytes. Many factors can contribute to the development of exhaustion. One of them is associated with a shift from a normal clonal expansion pathway to an altered one characterized by an early terminal differentiation of T cells. We propose that an altered T cell differentiation and proliferation sequence can naturally result from a spatial separation of the signaling events delivered via TCR, IL-2 and type I IFN receptors. Indeed, the spatial overlap of the concentration fields of extracellular IL-2 and IFN in lymph nodes changes dynamically due to different migration patterns of APCs and CD4 + T cells secreting them. CONCLUSIONS: The proposed hybrid mathematical model of the immune response represents a novel analytical tool to examine challenging issues in the spatio-temporal regulation of cell growth and differentiation, in particular the effect of timing and location of activation signals.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Bouchnita A, Bocharov G, Meyerhans A, Volpert V. Hybrid approach to model the spatial regulation of T cell responses. BMC Immunol. 2017 Jun 21;18(Suppl 1):29. DOI: 10.1186/s12865-017-0205-0
  • dc.identifier.doi http://dx.doi.org/10.1186/s12865-017-0205-0
  • dc.identifier.issn 1471-2172
  • dc.identifier.uri http://hdl.handle.net/10230/33067
  • dc.language.iso eng
  • dc.publisher BioMed Centralca
  • dc.relation.ispartof BMC Immunology. 2017 Jun 21;18(Suppl 1):29
  • dc.rights © The Author(s). 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.title Hybrid approach to model the spatial regulation of T cell responsesca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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