Age dependent selection against HPRT deficient T lymphocytes in the HPRT+/- heterozygous mouse

The fraction of HPRT deficient T lymphocytes was measured in the HPRT+/- female mouse between birth and an age of about 2 years. The animals were the F1 offspring of the HPRT deficient strain 129MF1 and HPRT competent C57BL/6J-mice. T lymphocytes from spleen were cloned in vitro and HPRT deficient clones were detected by double-labeling with [H-3]thymidine and [C-14]hypoxanthine. During the first weeks of life the fraction of deficient lymphocytes sharply decreases from about 50% at birth to 10-30% at an age of 10 weeks. In adult animals the fraction of HPRT deficient T cells smoothly further decreases to values about 10% at 80-90 weeks. The equation lambda(t) = [0.547 x exp(-0.405 x t)] + [0.453 X exp(-0.0116 x t)] was found to be a good approximation of the time course of HPRT deficient cells in spleen; lambda(t) is the fraction of deficient cells per competent cell and t is the age of animals in weeks. It is postulated that the selection against HPRT deficient T lymphocytes is the consequence of the reduced proliferative capacity of HPRT deficient cells (= selection factor). The time course of the ratio of deficient cells can be described as a function of the proliferation rate of the HPRT competent T cells and this selection factor. The sharp initial decrease is explained by a high selection pressure against HPRT deficient cells in young animals when the proliferation rate of the expanding T cell population is high and when T cells proliferate in the bone marrow. In adult animals the selection pressure against HPRT deficient cells is reduced, since T cells arise in general in peripheral lymphatic organs, where the salvage pathway is of lesser importance compared to the de novo purine synthesis. Implications of the selection against HPRT deficient lymphocytes for the widely used HPRT mutation assay are discussed.