Comprehensive Assessment and Mathematical Modeling of T Cell Population Dynamics and Homeostasis

Abstract

Our current view of T cell differentiation and population dynamics is assembled from pieces of data obtained from separate experimental systems and is thus patchy. We reassessed homeostasis and dynamics of T cells 1) by generating a mathematical model describing the spatiotemporal features of T cell differentiation, and 2) by fitting this model to experimental data generated by disturbing T cell differentiation through transient depletion of dividing T cells in mice. This specific depletion was obtained by administration of ganciclovir to mice expressing the conditional thymidine kinase suicide gene in T cells. With this experimental approach, we could derive quantitative parameters describing the cell fluxes, residence times, and rates of import, export, proliferation, and death across cell compartments for thymocytes and recent thymic emigrants (RTEs). Among other parameters, we show that 93% of thymocytes produced before single-positive stages are eliminated through the selection process. Then, a postselection peripheral expansion of naive T cells contributes three times more to naive T cell production than the thymus, with half of the naive T cells consisting of dividing RTEs. Altogether, this work provides a quantitative population dynamical framework of thymocyte development, RTEs, and naive T cells.

Immune reconstitution after cord blood transplants supported by coinfusion of mobilized hematopoietic stem cells from a third party donor

“…[11][12][13] Recent thymic emigrates (RTE) are T cells of naive phenotype, bearers of sjTRECs. A high correlation between the number of naive cells characterized by a CD45 þ RA þ CD31 þ phenotype and the number of CD4 þ cells bearing sjTRECs has been well documented, although numbers of sjTREC bearing cells in peripheral blood reflect a balance between thymic activity and the dilution effect of later divisions of the RTE.…”

“…In addition, our data on the course of recovery of cells of naive, effector and memory phenotypes within the CD3 þ CD4 þ and CD3 þ CD8 þ subpopulations are consistent with expansion of naive RTE generated in the recipient's thymus from the CB-HSC, that could result from the combined effects of the post-transplant lymphopenic environment (homeostatic expansion) and exposure to antigenic stimuli. [11][12][13] This could be an explanation for the observed lagging recovery of the absolute numbers of circulating cells of naive phenotype relative to the faster recovery of the committed (effector and memory) subsets, despite a maintained thymic cell output that, estimated on the basis of levels of sjTRECs, is not poorer than in normal infantile and adult controls. The observed late initiation of the T-cell recovery in our patients does not support an initial predominant contribution of the expansion of the naive T cells infused Figure 9 CMV-specific cells.…”

Immunodepression and Immunosuppression During Aging

“…The mathematical modelling of these experimental data, showing depletion and repletion of T cells compartment led us to evaluate the impact of dividing cell depletion treatment on T cells, the time necessary to return to pre-treatment values. Moreover, it allows to estimate parameters values at the steady state describing the continuous T cell differentiation, fluxes, cell division in the thymus and spleen of young adult mice (Thomas-Vaslin, Altes et al 2008). Figure 4 depicts the results of this model in young FVB mice and estimation of T cell composition in old mice from our experimental data.…”

“…Then, recent thymic emigrants (RTE) enter the spleen, divide and fill the Long-Lived naïve compartment. Antigenic stimulations trigger naïve cells to differentiate in antigenexperimented T cells (details on the model are in Thomas-Vaslin, Altes et al 2008). In old mice, the thymus was involuted, thus the naïve T cell is considerably reduced while the population of Ag-experiment T cells had increased following chronic antigenic challenges.…”

The Unconventionality of Nature: Biology, from Noise to Functional Randomness

“…Even more so, the about 10 9 leukocytes in the immune system, yet another large number, are effective exactly because of their variety and diversity: they are produced as a result of variability generators (Buiatti and Buiatti 2004) and subsequently selected when binding antigens. The immune system is a true evolutionary system within an organism, where diversity within each leukocytes' population, and between populations, is at the core of its functionality and is enhanced by selection (Thomas et al 2008 ). Thus, variability, which fluctuates over about 10 15 potentially different cell receptors, is the opposite of noise to be averaged out.…”