Heterogeneity in thymic emigrants: implications for thymectomy and immunosenescence

Abstract

The development of mature, antigen-inexperienced (naive) T cells begins in the thymus and continues after export into the periphery. Post-thymic maturation of naive T cells, in humans, coincides with the progressive loss of markers such as protein tyrosine kinase 7 (PTK7) and platelet endothelial cell adhesion molecule-1 (CD31). As a consequence, subpopulations of naive T cells can be recognised raising questions about the processes that give rise to the loss of these markers and their exact relationship to recent thymic emigrants (RTE). Here, we combine a mathematical survival analysis approach and data from healthy and thymectomised humans to understand the apparent persistence of populations of 'veteran' PTK7 (+) T cells in thymectomised individuals. We show that a model of heterogeneity in rates of maturation, possibly linked to natural variation in TCR signalling thresholds or affinity for self-antigens, can explain the data. This model of maturation predicts that the average post-thymic age of PTK7 (+) T cells will increase linearly with the age of the host suggesting that, despite the immature phenotype, PTK7 (+) cells do not necessarily represent a population of RTE. Further, the model predicts an accelerated increase in the average post-thymic age of residual PTK7 (+) T cells following thymectomy and may also explain in part the prematurely aged phenotype of the naive T cell pool in individuals thymectomised early in life.

Figure 1. Model of post-thymic maturation of cells within the naive CD4⁺ T cell population.

Survivorship of PTK7⁺ T cells within the naive T cell pool reflects the proportion of cells that express PTK7, and are detectable in the blood, as a function of time since leaving the thymus (illustrative plot). Changes in the survivorship function might arise from maturation into PTK7⁻naive T cells, division, or death.

Figure 2. Experimental observations of PTK7⁺ T cells from Haines et al.

. A: Frequency of PTK7⁺ naive CD4⁺ T cells in healthy individuals aged 0 to 60 years. B: Frequency of PTK7⁺ naive CD4⁺ T cells before and after thymectomy in subjects aged 2 and 14 years.

Figure 3. Post-thymectomy dynamics of PTK7⁺ naive CD4⁺ T cells in a model where residual thymic production alone maintains cell numbers.

Residual thymic production of ∼15% and ∼45% is required to reproduce the observed persistence of PTK7⁺ T cells in subjects thymectomised at age 2 and 14 years, respectively. Each curve corresponds to a constant rate of maturation from PTK7⁺ to PTK7⁻ naive T cells, as described in legend. Filled circles: observations by Haines & colleagues .

Figure 4. Survivorship of circulating PTK7⁺ T cells estimated by bi-exponential (left column) and lognormal distributions (right column).

(A) PTK7 survivorship functions. Black lines: estimated survivorship using best-fit parameters. Grey regions: a family of feasible survivorship functions that encompass observations in both healthy and thymectomised individuals. (B–C) Decline in PTK7⁺ naive CD4⁺ T cells post-thymectomy predicted by survivorship functions and clinical observations following thymectomy at age 2 and 14 years (filled circles). (D) PTK7⁺ naive CD4⁺ T cell numbers in healthy individuals from birth to age 60 years simulated using feasible survivorship functions and independent estimates of thymic export . Experimental observations (filled circles) are as published by Haines et al. .

Figure 5. Homogeneous rate of PTK7+ T cell maturation.

(A–B) Decline in PTK7⁺ naive CD4⁺ T cells post-thymectomy predicted by a range of density-dependent functions and clinical observations made by Haines et al. . (C) Age-related change in PTK7+ T cells with age predicted by the same family of density-dependent maturation functions combined with independent estimates of thymic export . Filled circles are experimental observations from Haines et al. . Grey region: a family of functions defined by equation (9) (where ) that encompasses observation in thymectomised individuals aged 2 and 14 years.

Figure 6. PTK7⁺ dynamics in a healthy individual.

Post-thymic age distribution of PTK7⁺ naive CD4⁺ T cells, in typical 1, 10, 30 and 60 year olds, calculated using the homogeneous (blue) and heterogeneous (red) models. The homogeneous model predicts an exponential distribution of post-thymic age (mean post-thymic age ∼0.25 years in a 60 year old subject); the heterogeneous model predicts an increasingly broad post-thymic age distribution (and significant accumulation of veteran PTK7⁺ cells) in aged individuals (mean post-thymic age ∼15 years in a 60 year old subject).

Figure 7. Implications of thymectomy.

Post-thymic age distribution of PTK7⁺ naive CD4⁺ T cells at days 0, 50 and 100 following thymectomy in a 2 and 14 year old, calculated using the homogeneous (blue) and heterogeneous (red) models.

Figure 8. Implications of thymectomy.

Predicted size of the residual PTK7⁺ naive CD4⁺ T cell population following thymectomy at different ages, as a percentage of expected PTK7⁺ numbers in age-matched non-thymectomised individuals, according to the heterogeneous model (using best-fit parameters for a bi-exponential distribution guided by data from thymectomised individuals; , , ).