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Mathematical Modeling Reveals the Biological Program Regulating Lymphopenia-Induced Proliferation¹

Andrew Yates, Manoj Saini^*, Anne Mathiot^* and Benedict Seddon^2,*

^* Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom; and Department of Biology, Emory University, Atlanta, GA 30322

Recognition of peptide-MHC by the TCR induces T lymphocytes to undergo cell division. Although recognition of foreign peptide induces a program of cellular division and differentiation by responding T cells, stimulation by self-peptide MHC complexes in lymphopenic conditions induces a slower burst of divisions that may or may not be accompanied by effector differentiation. Although both responses are triggered by signals from the TCR, it is not known whether they represent distinct programs of cell cycle control. In this study, we use a mathematical modeling approach to analyze the proliferative response of TCR transgenic F5 T cells to lymphopenia. We tested two fundamentally different models of cell division: one in which T cells are triggered into an "autopilot" deterministic burst of divisions, a model successfully used elsewhere to describe T cell responses to cognate Ag, and a second contrasting model in which cells undergo independent single stochastic divisions. Whereas the autopilot model provided a very poor description of the F5 T cell responses to lymphopenia, the model of single stochastic divisions fitted the experimental data remarkably closely. Furthermore, this model proved robust because specific predictions of cellular behavior made by this model concerning the onset, rate, and nature of division were successfully validated experimentally. Our results suggest cell division induced by lymphopenia involves a process of single stochastic divisions, which is best suited to a homeostatic rather than differentiation role.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Medical Research Council (U.K.) and the National Institutes of Health.

² Address correspondence and reprint requests to Dr. B. Seddon, Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, London NW7 1AA, U.K. E-mail address: bseddon{at}nimr.mrc.ac.uk

³ Abbreviations used in this paper: LIP, lymphopenia-induced proliferation; flu, influenza; SM, Smith-Martin; GH, Gett-Hodgkin; WT, wild type.