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Discriminating between Different Pathways of Memory CD8⁺ T Cell Differentiation¹

Theoretical Biology, Utrecht University, Utrecht, The Netherlands; Krasnoyarsk Science Center, Krasnoyarsk, Russia; and Institute of Biophysics, Krasnoyarsk, Russia

Despite the rapid accumulation of quantitative data on the dynamics of CD8⁺ T cell responses following acute viral or bacterial infections of mice, the pathways of differentiation of naive CD8⁺ T cells into memory during an immune response remain controversial. Currently, three models have been proposed. In the "stem cell-associated differentiation" model, following activation, naive T cells differentiate into stem cell-like memory cells, which then convert into terminally differentiated short-lived effector cells. In the "linear differentiation" model, following activation, naive T cells first differentiate into effectors, and after Ag clearance, effectors convert into memory cells. Finally, in the "progressive differentiation" model, naive T cells differentiate into memory or effector cells depending on the amount of specific stimulation received, with weaker stimulation resulting in formation of memory cells. This study investigates whether the mathematical models formulated from these hypotheses are consistent with the data on the dynamics of the CD8⁺ T cell response to lymphocytic choriomeningitis virus during acute infection of mice. Findings indicate that two models, the stem cell-associated differentiation model and the progressive differentiation model, in which differentiation of cells is strongly linked to the number of cell divisions, fail to describe the data at biologically reasonable parameter values. This work suggests additional experimental tests that may allow for further discrimination between different models of CD8⁺ T cell differentiation in acute infections.

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 National Institutes of Health grants and by a Marie Curie Incoming International Fellowship of FP6 (to V.V.G.).

² Address correspondence and reprint requests to Dr. Vitaly V. Ganusov, Theoretical Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands. E-mail address: v.v.ganusov{at}uu.nl

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; SCAD, stem cell-associated differentiation; LD, linear differentiation; PD, progressive differentiation; AIC, Akaike’s An Information Criterion; CI, confidence interval; T_CM, central memory CD8⁺ T cell; T_EM, effector memory CD8⁺ T cell.