Phenotypic models of perfect adaptation by CD8+ T cells

T cells receive continuous antigenic stimulation in peripheral tolerance, cancer, and chronic infection. Persistent antigen exposure induces an initial cellular response. However, over time, T cells become unresponsive to the stimulus and cease activity, a behaviour known as adaptation. Although it is generally known that T cells adapt to persistent stimuli, the properties of this adaptation remain understudied. This thesis aims to characterize phenotypes of T cell adaptation and to suggest the possibility of relating these phenotypes to basic network models that produce adaptation. To better understand T cell adaptive behaviour, a plate-based T cell receptor system was used to expose cells to step changes in antigen dose. In response to persistent antigen exposure, T cells can display perfect adaptation in cytokine production with incomplete TCR downregulation. Increasing the antigen dose leads to further tuning of the surface TCR level, independent of previous antigen exposure, with limited additional cytokine production. Thus, partial TCR downregulation tunes to antigen dose and perfect adaptation is observed even with partial downregulation. If T cells are exposed to gradual, incremental increases in antigen dose rather than a single dose, the cells are similarly silenced. The experimental data was subsequently examined in the context of seven basic, preliminary models of adaptation. A model based on partial TCR downregulation with a second downstream mechanism aligns with experimental observations, suggesting the potential relevance of TCR downregulation. Clinically, T cell-modulating therapies often cause potent early cytokine production. As a proof-of-concept, I demonstrate that otelixizumab induces T cell adaptation as a non-pMHC stimulus. Further study of T cell adaptation is thus invaluable both to understanding T cell behaviour as well as therapeutic design.