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Journal of Virology, November 2001, p. 10663-10669, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10663-10669.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Recruitment Times, Proliferation, and Apoptosis Rates during the CD8+ T-Cell Response to Lymphocytic Choriomeningitis Virus

Rob J. De Boer,1,* Mihaela Oprea,2 Rustom Antia,3 Kaja Murali-Krishna,4 Rafi Ahmed,4 and Alan S. Perelson2

Theoretical Biology, Utrecht University, 3584 CH Utrecht, The Netherlands1; Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 875452; and Department of Biology3 and Emory Vaccine Center and Department of Microbiology and Immunology,4 Emory University, Atlanta, Georgia 30322

Received 15 March 2001/Accepted 11 August 2001

The specific CD8+ T-cell response during acute lymphocytic choriomeningitis virus (LCMV) infection of mice is characterized by a rapid proliferation phase, followed by a rapid death phase and long-term memory. In BALB/c mice the immunodominant and subdominant CD8+ responses are directed against the NP118 and GP283 epitopes. These responses differ mainly in the magnitude of the epitope-specific CD8+ T-cell expansion. Using mathematical models together with a nonlinear parameter estimation procedure, we estimate the parameters describing the rates of change during the three phases and thereby establish the differences between the responses to the two epitopes. We find that CD8+ cell proliferation begins 1 to 2 days after infection and occurs at an average rate of 3 day-1, reaching the maximum population size between days 5 and 6 after immunization. The 10-fold difference in expansion to the NP118 and GP283 epitopes can be accounted for in our model by a 3.5-fold difference in the antigen concentration of these epitopes at which T-cell stimulation is half-maximal. As a consequence of this 3.5-fold difference in the epitope concentration needed for T-cell stimulation, the rates of activation and proliferation of T cells specific for the two epitopes differ during the response and in combination can account for the large difference in the magnitude of the response. After the peak, during the death phase, the population declines at a rate of 0.5 day-1, i.e., cells have an average life time of 2 days. The model accounts for a memory cell population of 5% of the peak population size by a reversal to memory of 1 to 2% of the activated cells per day during the death phase.

* Corresponding author. Mailing address. Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Phone: 31 30 253 7650. Fax: 31 30 251 3655. E-mail: R.J.DeBoer{at}bio.uu.nl.

Journal of Virology, November 2001, p. 10663-10669, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10663-10669.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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