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* Université Pierre et Marie Curie-Paris 06, Unité Mixte de Recherche 7087, Biologie et Thérapeutique des Pathologies Immunitaires, Paris, France;
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7087, Biologie et Thérapeutique des Pathologies Immunitaires, Paris, France;
Population Biology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands; and
Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Agence Nationale de la Recherche sur le SIDA, Centre National de la Recherche Scientifique, Paris 6 University, Action Thématique Concertée Vieillissement Institut National de la Santé et de la Recherche Médicale, Netherlands Organisation for Scientific Research, and CompuVac.
2 Address correspondence and reprint requests to Dr. Véronique Thomas-Vaslin, Unité Mixte de Recherche 7087, Université Pierre et Marie Curie, Centre National de la Recherche Scientifique, CERVI Groupe Hospitalo-Universitaire Pitié-Salpêtrière, 83 Boulevard de l’Hôpital 75013 Paris, France. E-mail address: thomas{at}chups.jussieu.fr
3 V.T.-V. and H.K.A. contributed equally.
4 Current address: Centre for Infectious Disease Epidemiology, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands.
5 R.J.d.B. and D.K. contributed equally.
6 Abbreviations used in this paper: RTE, recent thymic emigrant; GCV, ganciclovir; DN, CD4–CD8– double negative; Ct, cycle threshold; LN, lymph node; DP, CD4+CD8+ double positive; SP, single positive; TK, HSV-1 thymidine kinase; Tx, thymectomy; 7AAD, 7-aminoactinomycin D.
7 The online version of this article contains supplemental material.
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