Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans

Liset Westera, Julia Drylewicz, Ineke den Braber, Tendai Mugwagwa, Iris van der Maas, Lydia Kwast, Thomas Volman, Elise H.R. van de Weg-Schrijver, István Bartha, Gerrit Spierenburg, Koos Gaiser, Mariëtte T. Ackermans, Becca Asquith, Rob J. de Boer, Kiki Tesselaar, José A.M. Borghans

Quantitative knowledge of the turnover of different leukocyte populations is a key to our understanding of immune function in health and disease. Much progress has been made thanks to the introduction of stable isotope labeling, the state-of-the-art technique for in vivo quantification of cellular life spans. Yet, even leukocyte life span estimates on the basis of stable isotope labeling can vary up to 10-fold among laboratories. We investigated whether these differences could be the result of variances in the length of the labeling period among studies. To this end, we performed deuterated water-labeling experiments in mice, in which only the length of label administration was varied. The resulting life span estimates were indeed dependent on the length of the labeling period when the data were analyzed using a commonly used single-exponential model. We show that multiexponential models provide the necessary tool to obtain life span estimates that are independent of the length of the labeling period. Use of a multiexponential model enabled us to reduce the gap between human T-cell life span estimates from 2 previously published labeling studies. This provides an important step toward unambiguous understanding of leukocyte turnover in health and disease.