Implications of thymectomy.

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

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

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Haines1" target="_blank">[<b>5</b>]</a><b>. </b><b>A:</b> Frequency of PTK7<b>⁺</b> naive CD4<b>⁺</b> T cells in healthy individuals aged 0 to 60 years. <b>B:</b> Frequency of PTK7<b>⁺</b> naive CD4<b>⁺</b> T cells before and after thymectomy in subjects aged 2 and 14 years.</p

Homogeneous rate of PTK7+ T cell maturation.

<p>(<b>A–B</b>) Decline in PTK7<b>⁺</b> naive CD4<b>⁺</b> T cells post-thymectomy predicted by a range of density-dependent functions and clinical observations made by Haines et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Haines1" target="_blank">[5]</a>. (<b>C</b>) 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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Bains2" target="_blank">[26]</a>. Filled circles are experimental observations from Haines et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Haines1" target="_blank">[5]</a>. Grey region: a family of functions defined by <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554.e040" target="_blank">equation (9</a>) (where ) that encompasses observation in thymectomised individuals aged 2 and 14 years.</p

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

<p>(<b>A</b>) 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>B–C</b>) Decline in PTK7<b>⁺</b> naive CD4<b>⁺</b> T cells post-thymectomy predicted by survivorship functions and clinical observations following thymectomy at age 2 and 14 years (filled circles). (<b>D</b>) PTK7<b>⁺</b> naive CD4<b>⁺</b> T cell numbers in healthy individuals from birth to age 60 years simulated using feasible survivorship functions and independent estimates of thymic export <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Bains2" target="_blank">[26]</a>. Experimental observations (filled circles) are as published by Haines et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049554#pone.0049554-Haines1" target="_blank">[5]</a>.</p

PTK7⁺ dynamics in a healthy individual.

<p>Post-thymic age distribution of PTK7<b>⁺</b> naive CD4<b>⁺</b> T cells, in typical 1, 10, 30 and 60 year olds, calculated using the homogeneous (<b>blue</b>) and heterogeneous (<b>red</b>) 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<b>⁺</b> cells) in aged individuals (mean post-thymic age ∼15 years in a 60 year old subject).</p

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

<p>Survivorship of PTK7<b>⁺</b> 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.</p

Implications of thymectomy.

<p>Predicted size of the residual PTK7<b>⁺</b> naive CD4<b>⁺</b> T cell population following thymectomy at different ages, as a percentage of expected PTK7<b>⁺</b> 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; , , ).</p

Data taken from van Santen <i>et al.</i>[16].

<p>Absolute number of clonotype positive (T, red circles) and (T, blue circles) thymocytes in tetracycline-treated TAND mice, as a function of the relative expression level of TIM RNA in the thymus of these animals. Control animals lacked either the transactivator or reporter transgene.</p

Model descriptions of the data.

<p>Representative descriptions of the data by the models. T in blue, T in red. <b>Panel A</b>; the one-hit model in which fate decisions are re-evaluated after single TCR-pMHC contacts. The dotted curves, ; dashed curves, . <b>Panel B</b>; the model; <b>Panel C</b>; the two-phase model with .</p

The two-phase model.

<p>In this instance, TCR sensitivity is assumed to increase during development, such that an encounter with the agonist ligand TIM delivers a signal that initiates T development early in selection (phase A) but causes deletion if encountered later (phase B).</p