Generation of the natural killer cell repertoire: The sequential vs. the two-step selection model

Natural killer (NK) cells are lymphocytes which can kill tumor and virus-infected cells, and mediate acute rejection of bone marrow grafts. NK-cell killing is directed primarily at target cells which do not express sufficient levels of self-major histocompatibility complex (MHC) class-I molecules. Inhibition of lysis of self-MHC-expressing target cells is mediated via inhibitory receptors on the NK cell, which bind to MHC molecules. Each NK cell expresses only a subset of all its inhibitory receptor gene repertoire, which may bind to only a subset of the self-MHC molecules expressed by other cells of the organism. Two conceptual models have been proposed to explain the process of NK cell ‘education’ in which these cells adapt, during their development, to the self-MHC environment: the two-step selection and the sequential models. In this manuscript we develop mathematical and computational models of the process of NK cell development and education, which implement the two conceptual models. We use this theoretical framework to examine the available data on NK cell repertoire compositions, and evaluate the degree these data support either of the two conceptual models. We show that the data published so far on NK cell receptor expression patterns is insufficient to refute either model, since data on NK cell receptor binding affinities to MHC is also needed. However, the models allow us to make predictions on these binding affinities, which can later be tested experimentally.