Natural killer cells and their relationship to T-cells: hypothesis on the role of T-cell receptor gene rearrangement on the course of adaptive differentiation.

We propose that the differentiation of NK cells and the differentiation of T-cells are intimately interrelated, although mature effector cells of each type usually can be distinguished from each other. The divergence in their characteristics may be initiated upon rearrangement of the genes for the T-cell receptor, with a subsequent inverse relationship between the expression of T-cell receptors and NK cell receptors. However, an essential element of our hypothesis is that the differentiation of these cells is partially adaptive rather than rigidly preprogrammed. This concept is considerably more compatible with the phenotypic plasticity which has been exhibited by cultured cells in general and by T-cells and LGL in particular. We suggest that the nature of the self environment has a major influence on the direction of development of precursor cells, both by controlling the ratio between the rates of proliferation and differentiation at each stage of maturation and by inducing quantitative or qualitative changes in the pattern of gene expression. As maturation proceeds, the degree of plasticity probably decreases, possibly due to inheritable epigenetic changes in the genome. Our hypothesis accommodates most if not all of the available experimental data on the phenotypic, genetic, and functional interrelationships between NK cells and T-cells. In particular, it accounts for the extensive and controversial data on cultured cell lines with varying degrees of similarity to T-cells and to NK cells. In addition, our model emphasizes the inherent limitations in utilizing such data from cell lines as the basis for drawing conclusions on the properties of cells developing under physiological conditions. Most importantly, our hypothesis leads to a series of experimentally testable predictions, which should provide considerably greater insight into the ontogeny of NK cells and their relationship to the T-cell lineage.