Quantifying Thymic Export: Combining Models of Naive T Cell Proliferation and TCR Excision Circle Dynamics Gives an Explicit Measure of Thymic Output

Abstract

Understanding T cell homeostasis requires knowledge of the export rate of new T cells from the thymus, a rate that has been surprisingly difficult to estimate. TCR excision circle (TREC) content has been used as a proxy for thymic export, but this quantity is influenced by cell division and loss of naive T cells and is not a direct measure of thymic export. We present in this study a method for quantifying thymic export in humans by combining two simple mathematical models. One uses Ki67 data to calculate the rate of peripheral naive T cell production, whereas the other tracks the dynamics of TRECs. Combining these models allows the contributions of the thymus and cell division to the daily production rate of T cells to be disentangled. The method is illustrated with published data on Ki67 expression and TRECs within naive CD4+ T cells in healthy individuals. We obtain a quantitative estimate for thymic export as a function of age from birth to 20 years. The export rate of T cells from the thymus follows three distinct phases, as follows: an increase from birth to a peak at 1 year, followed by rapid involution until ∼8 years, and then a more gradual decline until 20 years. The rate of involution shown by our model is compatible with independent estimates of thymic function predicted by thymic epithelial space. Our method allows nonintrusive estimation of thymic output on an individual basis and may provide a means of assessing the role of the thymus in diseases such as HIV.

Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age

“…The total T-cell population size for a young human adult is ∼3 × 10 11 ; the percentage of this population that is naive decreases with age from ∼50% to ∼30% for CD4 cells (19). Further, thymic involution, which occurs at a rate of at least 3% per year until age 40, and 1% thereafter (14,41), should lead to a corresponding decline in the rate of thymic emigrants. These results are consistent with experiments showing that thymic emigration plays a minor role relative to T-cell turnover for the maintenance of naive T cells (20).…”

Reduced T-Cell Thymic Export Reflected by sj-TREC in Patients with Coronary Artery Disease

“…In this study, the result that reduced sj-TREC copy number from total T lymphocytes in CAD patients was consistent with the previously reported reduced proportion of naïve T cells 13) . And the proportion of naïve T cells was ever used to reflect thymic output 48) . In addition, negative correlation between sj-TREC and NLR revealed that patients with higher NLR had more severe inflammatory status, more complex plaques 29,49) , and lower output of lymphocytes, such as T cells from the thymus.…”

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

“…10,[42][43][44] Our observation also supports the need for combining different markers (ie, TREC content and Ki67 expression) for a correct thymic output evaluation in human beings, as recently suggested by different authors. 45,46 In summary, our data show that T-cell reconstitution after GT for ADA-SCID, like allogeneic BMT, is driven by de novo thymopoiesis, as well as by homeostatic expansion of naive and memory T cells, especially in the first months after treatment. The latter mechanism could explain the telomere shortening observed in T cells from both GT and BMT-treated patients, whereas normal telomere length in the myeloid and BM compartment indicates no difference between the autologous and allogeneic procedure at the stem/progenitor cell level.…”