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.
Bibliographical noteFunding Information:
The author would like to express her gratitude to all the past and present colleagues and students who have contributed to the studies reviewed in this manuscript. The author is also grateful to Dr Shelley Schwarzbaum for a critical reading of the manuscript, and to Ms Hanna Edelman for help in manuscript and figure preparation. The work reviewed here was supported in parts by grants to the author, including (chronologically) a grant from the Brookdale Institute of Gerontology and Adult Human Development in Israel, and Eshel Association for the Planning and Development of Services for the Aged in Israel; a Director’s Postdoctoral Fellowship, Los Alamos National Laboratory, USA; NIH Grant AI10227-01; the Yigal Alon Fellowship; the Israel Science Foundation grant number 759/01-1; a Human Frontiers Science Program grant; a Swedish Foundation for Strategic Research grant funding the Strategic Research Center for studies on Integrative Recognition in the Immune System (IRIS), Karolinska Institute, Stockholm, Sweden; and a project grant from the Israel Cancer Research Fund.
- B and T lymphocytes
- Cellular differentiation
- Cellular proliferation
- Computational modeling
- Natural killer cells
- Repertoire development