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Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 T Cells: Parameter Estimation Based on 5-Bromo-2'-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow¹

Elisabetta Parretta^*, Giuliana Cassese, Angela Santoni^*,, John Guardiola, Antonia Vecchio and Francesca Di Rosa^2,,

^* Department of Experimental Medicine, University of Rome "La Sapienza," Rome, Italy; Institute of Genetics and Biophysics, "Adriano Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Naples, Italy; Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, Rome, Italy; and Istituto per le Applicazioni del Calcolo "M. Picone," Consiglio Nazionale delle Ricerche, Naples, Italy

To study naive and memory CD8 T cell turnover, we performed BrdU incorporation experiments in adult thymectomized C57BL/6 mice and analyzed data in a mathematical framework. The following aspects were novel: 1) we examined the bone marrow, in addition to spleen and lymph nodes, and took into account the sum of cells contained in the three organs; 2) to describe both BrdU-labeling and -delabeling phase, we designed a general mathematical model, in which cell populations were distinguished based on the number of divisions; 3) to find parameters, we used the experimentally determined numbers of total and BrdU⁺ cells and the BrdU-labeling coefficient. We treated mice with BrdU continuously via drinking water for up to 42 days, measured by flow cytometry BrdU incorporation at different times, and calculated the numbers of BrdU⁺ naive (CD44^int/low) and memory (CD44^high) CD8 T cells. By fitting the model to data, we determined proliferation and death rates of both subsets. Rates were confirmed using independent sets of data, including the numbers of BrdU⁺ cells at different times after BrdU withdrawal. We found that both doubling time and half-life of the memory population were 9 wk, whereas for the naive subset the doubling time was almost 1 year and the half-life was roughly 7 wk. Our findings suggest that the higher turnover of memory CD8 T cells as compared with naive CD8 T cells is mostly attributable to a higher proliferation rate. Our results have implications for interpreting physiological and abnormal T cell kinetics in humans.

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 Associazione Italiana per la Ricerca sul Cancro.

² Address correspondence and reprint requests to Dr. Francesca Di Rosa, Consiglio Nazionale delle Ricerche, c/o Department of Experimental Medicine, University of Rome "La Sapienza", viale Regina Elena 324, 00161 Rome, Italy. E-mail address: francesca.dirosa{at}uniroma1.it

³ Abbreviations used in this paper: BM, bone marrow; LN, lymph node.