Modeling Natural Killer Cell Development and Repertoire Formation
by
Ramit Mehr
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Coauthors: Mali Salmon-Divon, Sofia Johansson, Maria Johansson, Yishai Pickman, Marjet Elemans, Petter Höglund, and Ramit Mehr

NK cells are able to recognize and reject cells lacking expression of self- MHC class I molecules. Inhibition of lysis is mediated by inhibitory receptors expressed by NK cells, such as the murine Ly49 receptors, which bind to MHC class I molecules. NK cells adapt to the self-MHC environment by a process ensuring that each cell expresses at least one self-specific inhibitory receptor but not too many. Two models have been proposed to account for the development of a useful Ly49 repertoire. The two-step selection model proposes a stochastic initial receptor expression combined with selection of cells expressing appropriate receptor compositions. The sequential model proposes that NK cells sequentially express Ly49 receptors and continue to do so until an interaction of sufficient magnitude between a Ly49 receptor and self-class I MHC occurs. These two models predict different repertoire compositions under various conditions. The complexity of experimental observations on NK cell repertoire development necessitates the application of theoretical techniques in order to elucidate the principles underlying this development and evaluate the proposed models. We conducted mathematical modeling and computer simulation studies of each NK cell education model, fitting them to published (Salmon-Divon et al, 2003a, b; 2004) and newly generated (Salmon-Divon et al, in preparation) experimental data. Our results favor the two-step selection model over the sequential model, and raise several questions, which will be addressed in our future studies combining experiments, mathematical modeling and computer simulations.

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Date received: May 10, 2008