Modulation of T cell activation by localized K? accumulation at the immunological synapse--a mathematical model.

摘要

The response of T cells to antigens (T cell activation) is marked by an increase in intracellular Ca2? levels. Voltage-gated and Ca2?-dependent K? channels control the membrane potential of human T cells and regulate Ca2? influx. This regulation is dependent on proper accumulation of K? channels at the immunological synapse (IS) a signaling zone that forms between a T cell and antigen presenting cell. It is believed that the IS provides a site for regulation of the activation response and that K? channel inhibition occurs at the IS, but the underlying mechanisms are unknown. A mathematical model was developed to test whether K? efflux through K? channels leads to an accumulation of K? in the IS cleft, ultimately reducing K? channel function and intracellular Ca2? concentration ([Ca2?](i)). Simulations were conducted in models of resting and activated T cell subsets, which express different levels of K? channels, by varying the K? diffusion constant and the spatial localization of K? channels at the IS. K? accumulation in the IS cleft was calculated to increase K? concentration ([K?]) from its normal value of 5.0 mM to 5.2-10.0 mM. Including K? accumulation in the model of the IS reduced calculated K? current by 1-12% and consequently, reduced calculated [Ca2?](i) by 1-28%. Significant reductions in K? current and [Ca2?](i) only occurred in activated T cell simulations when most K? channels were centrally clustered at the IS. The results presented show that the localization of K? channels at the IS can produce a rise in [K?] in the IS cleft and lead to a substantial decrease in K? currents and [Ca2?](i) in activated T cells thus providing a feedback inhibitory mechanism during T cell activation.