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

Abstract

Key Points• Life span estimates can be sensitive to the duration of stable isotope label administration, explaining discrepancies in the literature.• Multiexponential models are needed to obtain reliable leukocyte life span estimates.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. (Blood. 2013;122(13):2205-2212

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Based on the reported doubling time of leukemia cells in log phase culture at approximately 1.5 days, 20  k g was fixed at 0.02 1/hr for all in vitro cytotoxicity data when target cell growth information was unavailable. Based on the literature reported T cell turnover rate at 0.02 1/day, 21 k out of effectors cells was fixed as 0.000833 1/hour.…”

“…21 The killing of target cells is driven by TBE complex per target cell (TBEPC). The concentrations of T cells and target cells were different across the datasets used for model development.…”

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

“…Simulations predict sharp decline of effective clonal diversity. We simulated the population dynamics of human naive T cells as described in the text and Materials and Methods, based on experimental estimates of the Hayflick limit (22,29), the bias in thymic production of different T-cell clones (46,47), and the rates of thymopoeisis (9,18,19,21), T cell turnover (42,43,45), and telomere attrition (31,48). We set the bias in thymic production of different T cell clones to w = 0.01.…”

“…Each p value was computed by permuting randomly the corresponding estimates of effective clonal diversity and then comparing the resulting correlation coefficient to that obtained using unpermuted estimates. with those cited above (45). Therefore, we assume that T cells are lost from the population at the average rate d t = 0.15% day 21 .…”

“…We propose that over time this dynamic will cause a chain reaction of cell loss, which will suddenly drive most T cell clones to extinction. In the following, we will demonstrate, using stochastic numerical simulations based on experimental data (18,21,22,28,29,31,38,(42)(43)(44)(45)(46)(47)(48), that this model provides a plausible explanation for the sharp decline of effective clonal diversity observed in elderly humans.…”