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IL-2 Regulates Expansion of CD4⁺ T Cell Populations by Affecting Cell Death: Insights from Modeling CFSE Data¹

Vitaly V. Ganusov², Dejan Milutinovi and Rob J. De Boer

Theoretical Biology, Utrecht University, Utrecht, The Netherlands

It is generally accepted that IL-2 influences the dynamics of populations of T cells in vitro and in vivo. However, which parameters for cell division and/or death are affected by IL-2 is not well understood. To get better insights into the potential ways of how IL-2 may influence the population dynamics of T cells, we analyze data on the dynamics of CFSE-labeled polyclonal CD4⁺ T lymphocytes in vitro after anti-CD3 stimulation at different concentrations of exogenous IL-2. Inferring cell division and death rates from CFSE-delabeling experiments is not straightforward and requires the use of mathematical models. We find that to adequately describe the dynamics of T cells at low concentrations of exogenous IL-2, the death rate of divided cells has to increase with the number of divisions cells have undergone. IL-2 hardly affects the average interdivision time. At low IL-2 concentrations 1) fewer cells are recruited into the response and successfully complete their first division; 2) the stochasticity of cell division is increased; and 3) the rate, at which the death rate increases with the division number, increases. Summarizing, our mathematical reinterpretation suggests that the main effect of IL-2 on the in vitro dynamics of naive CD4⁺ T cells occurs by affecting the rate of cell death and not by changing the rate of cell division.

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 Human Frontier Science Program Grant RGP0010/2004, Netherlands Organization for Scientific Research Grant 016.048.603, and Marie Curie Incoming International Fellowship (FP6).

² Address correspondence and reprint requests to Dr. Vitaly V. Ganusov, Utrecht University, Padualaan 8, Utrecht, Netherlands. E-mail address: v.v.ganusov{at}uu.nl

³ Abbreviations used in this paper: SM, Smith-Martin; TLE, thymidine-labeling experiment.

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