How Do Interactions Between Cytotoxic T Cells and Targets Shape the Functional Response Describing Target Cell Death?

Abstract

Cytotoxic T lymphocytes (CTLs) play an important role in the control of virus infections and tumors by killing virus-infected and tumor cells. An important parameter in determining the efficiency of CTL-mediated control is the rate at which they kill the target cells, and how it varies with the CTL and target cell densities (i.e., functional response of CTL-mediated killing). In the first part of this thesis, we investigate the functional response of CTL-mediated killing of target cells, and how various factors like the mode of CTL-target cell interactions, stability of the conjugates, and tissue dimensionality, influence the functional response. We employ computational and mathematical models to determine the expected general functional response from the various CTL-target cell interactions. Finally, in the second part of the thesis, we analyze the experimental data from two cytotoxicity assays to determine which functional responses occur under different experimental conditions. In all the studies of this thesis, we consistently find that a double saturation (DS) model with two saturation constants (one for CTLs and another for target cells) describes the CTL-mediated killing well. This is true for different modes of interactions, in spatially homogeneous as well as heterogeneous gels, in 2D as well as 3D spaces, and in densely as well as sparsely populated environments. We showed that this DS model can be mechanistically derived for some cases, and that in the other cases it still provides a semi-mechanistic description. Our results suggest that the extent of saturation in CTLs and targets is determined by the stability of the conjugates, spatial dimensionality of the tissue, and mode of CTL-target interactions. The relative differences in the two saturation constants can help us identify underlying CTL-target cell interactions, but factors like the occurrence of a transient to the steady state and spatial heterogeneity of the environment can confound this inference. Nevertheless, any significant deviations from the DS model noticed in cytotoxicity assays do suggest that additional mechanisms are at play. In summary, we propose that the DS model is an excellent default model to describe CTL-mediated killing of target cells.