title: A Sigmoid Functional Response Emerges When Cytotoxic T Lymphocytes Start Killing Fresh Target Cells.
abstract: Cytotoxic T lymphocyte (CTL)-mediated killing involves the formation of a synapse with a target cell, followed by delivery of perforin and granzymes. Previously, we derived a general functional response for CTL killing while considering that CTLs form stable synapses (i.e., single-stage) and that the number of conjugates remains at steady state. However, the killing of target cells sometimes requires multiple engagements (i.e., multistage). To study how multistage killing and a lack of steady state influence the functional response, we here analyze a set of differential equations as well as simulations employing the cellular Potts model, in both cases describing CTLs that kill target cells. We find that at steady state the total killing rate (i.e., the number of target cells killed by all CTLs) is well described by the previously derived double saturation function. Compared to single-stage killing, the total killing rate during multistage killing saturates at higher CTL and target cell densities. Importantly, when the killing is measured before the steady state is approached, a qualitatively different functional response emerges for two reasons: First, the killing signal of each CTL gets diluted over several targets and because this dilution effect is strongest at high target cell densities; this can result in a peak in the dependence of the total killing rate on the target cell density. Second, the total killing rate exhibits a sigmoid dependence on the CTL density when killing is a multistage process, because it takes typically more than one CTL to kill a target. In conclusion, a sigmoid dependence of the killing rate on the CTLs during initial phases of killing may be indicative of a multistage killing process. Observation of a sigmoid functional response may thus arise from a dilution effect and is not necessarily due to cooperative behavior of the CTLs.
authors.affiliation: Theoretical Biology, Utrecht University, Utrecht, the Netherlands. Electronic address: skgadhamsetty@gmail.com.
authors.forename: Saikrishna
authors.initials: S
authors.lastname: Gadhamsetty
authors.affiliation: Department of Computational and Systems Biology, John Innes Centre, Norwich, United Kingdom.
authors.forename: Athanasius F M
authors.initials: AFM
authors.lastname: Marée
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Joost B
authors.initials: JB
authors.lastname: Beltman
authors.affiliation: Theoretical Biology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: de Boer
mesh_terms: D002452:Cell Count; D016923:Cell Death; D008954:Models, Biological; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*