Quantifying the development of the peripheral naive CD4+ T-cell pool in humans

Abstract

What are the rules that govern a naive T cell's prospects for survival or division after export from the thymus into the periphery? To help address these questions, we combine data from existing studies with robust mathematical models to estimate the absolute contributions of thymopoiesis, peripheral division, and loss or differentiation to the human naive CD4+ T-cell pool between the ages of 0 and 20 years. Despite their decline in frequency in the blood, total body numbers of naive CD4+ T cells increase throughout childhood and early adulthood. Our analysis shows that postthymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved with age; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens. We also show that the expected residence time of naive T cells increases with time. The naive CD4+ T-cell population thus becomes progressively less dynamic with age. Together with other studies, our results suggest a complex picture of naive T-cell homeostasis in which population size, time since export from the thymus, or time since the last division can influence a cell's prospects for survival or further divisions.

Figure 1

Naive T-cell and TREC dynamics. TRECs (small black circles) are present at low frequencies in naive T cells leaving the thymus and are preserved in total numbers by cell division in the periphery. Assuming the rate of intracellular degradation of TRECs is negligible, loss of TRECs from the naive pool is caused only by loss of naive cells, either by death or differentiation into effector phenotype.

Figure 2

Estimating total body naive CD4⁺ T cells as a function of age. (A) Body weight as a function of age, from Kuczmarski et al. (B) Blood volume as a function of age, estimated from panel A and the regression relation between weight and blood volume in Linderkamp et al (Appendix). (C) Mean naive CD4⁺ T-cell density in blood with age, using the relation in Huenecke et al (Appendix). (D) Estimated total body naive CD4⁺ T-cell numbers, using the data in panels B and C. Panels A, B, and D show the mean, 2.5 and 97.5 percentiles at the population level; panel C shows the mean and its associated 95% confidence interval.

Figure 3

TREC dynamics in the young. (A) Measurements of TRECs per naive CD4⁺ T cell, from Douek et al. (B) Estimated distribution of total TRECs in the naive CD4⁺ T-cell pool across the human population with age, showing the mean, 2.5 and 97.5 percentiles.

Figure 4

Estimated mean rates. The estimated mean rates (black lines) of successful naive CD4⁺ T-cell division, ρ(t) (A) and loss, δ(t) (B) as functions of age, t. The 2.5 and 97.5 percentiles are shown in gray. A proliferation rate of, for example, 0.02 means that approximately 2% of cells divide per day.

Figure 5

Estimated mean absolute daily contributions of thymic export (solid line), peripheral division (dashed), and peripheral loss (dotted) to the dynamics of the naive CD4⁺ T-cell pool with age, using the lower bound on the TREC content of RTEs; c = 0.25.

Figure 6

Scaling of naive T-cell densities with age. (A) Estimated mean naive CD4⁺ T cells per kilogram of body mass as a function of age (black line), with 2.5 and 97.5 percentiles at the population level (gray lines). (B) Estimated dependence of mean naive CD4⁺ T-cell density (cells/kg) on log₁₀ body mass.

Figure 7

Assessing the sensitivity of our analysis to the assumption that 2% of naive cells are found in blood. (A) Total body naive population as a function of age. (B) Predicted rate of proliferation. (C) Predicted rate of loss. (D) Predicted absolute number of cells exported by thymus (solid line), produced in periphery (dashed line), and lost from naive pool (gray line, fixed 2% for all ages; dotted line, proportion of cells in the blood increases linearly from 1% at birth to 2% at age 20).