Determining control parameters for dendritic cell-cytotoxic T lymphocyte interaction.
Dendritic cells (DC) are potent immunostimulatory cells facilitating antigen transport to lymphoid tissues and providing efficient stimulation of T cells. A series of experimental studies in mice demonstrated that cytotoxic T lymphocytes (CTL) can be efficiently induced by adoptive transfer of antigen-presenting DC. However, the success of DC-based immunotherapeutic treatment of human cancer, for example, is still limited because the details of the regulation and kinetics of the DC-CTL interaction are not yet completely understood. Using a combination of experimental mouse studies, mathematical modeling, and nonlinear parameter estimation, we analyzed the population dynamics of DC-induced CTL responses. The model integrates a predator-prey-type interaction of DC and CTL with the non-linear compartmental dynamics of T cells. We found that T cell receptor avidity, the half-life of DC, and the rate of CTL-mediated DC-elimination are the major control parameters for optimal DC-induced CTL responses. For induction of high avidity CTL, the number of adoptively transferred DC was of minor importance once a minimal threshold of approximately 200 cells per spleen had been reached. Taken together, our study indicates that the availability of high avidity T cells in the recipient in combination with the optimal application regimen is of prime importance for successful DC-based immunotherapy.
Ludewig
Burkhard
B
Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland. burkhard.ludewig@kssg.ch
Krebs
Philippe
P
Junt
Tobias
T
Metters
Helen
H
Ford
Neville J
NJ
Anderson
Roy M
RM
Bocharov
Gennady
G
D000818:Animals; D002450:Cell Communication; D003713:Dendritic Cells / Q000502:physiology*; D008433:Mathematics; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*