Comparing antigen-independent mechanisms of T cell regulation

Key features of the kinetics of T lymphocyte proliferative responses are remarkably insensitive to the nature of the antigenic stimulus. This consistency suggests the presence of an antigen-independent mechanism regulating T cell clonal expansion. Knowledge of such a mechanism could allow us to modulate T helper cell (CD4+) and cytotoxic T cell (CD8+) responses more effectively. Using a simple mathematical model of T cell proliferation and death, we investigate a variety of plausible mechanisms and compare the model predictions to experimental data from the literature. We find that irrespective of the details of the mechanism, rates of apoptosis must progressively increase to control a T cell response. If apoptosis is mediated by cell–cell contact this alone is sufficient to regulate both CD4+ and CD8+ T cell responses. Proliferation of both T cell subsets can also be regulated by an internal programme, by cytokine signalling, or by an APC-mediated route. To regulate CD8+ T cells these mechanisms must change both apoptosis and division rates, and this change must occur with time not division number.