IL-2 regulates expansion of CD4+ T cell populations by affecting cell death: insight from modeling CFSE data

Abstract

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.