Feedback loops, reversals and nonlinearities in lymphocyte development

Systems of differentiating cells are often regarded by experimental biologists as unidirectional processes, in which cells spend a fixed time at each successive developmental stage. However, mathematical modeling has in several cases revealed that differentiating cell systems are more complex than previously believed. For example, non-linear transitions, feedback effects, and even apparent reversals have been suggested by our studies on models for the development of lymphocytes and their receptor repertoires, and are reviewed in this paper. These studies have shown that cell population growth in developing lymphocyte subsets is usually nonlinear, as it depends on the density of cells in each compartment. Additionally, T cell development has been shown to be subject to feedback regulation by mature T cell subsets, and B cell development has been shown to include a phenotypic reflux from an advanced to an earlier developmental stage. The challenges we face in our efforts to understand how the repertoires of these cells are generated and regulated are also discussed here.