Modulation of T cell activation by localized K+ accumulation at the immunological synapse—A mathematical model

Geoffrey V. Martin, Yeoheung Yun, Laura Conforti
2012 Journal of Theoretical Biology  
The response of T cells to antigens (T cell activation) is marked by an increase in intracellular Ca 2+ levels. Voltage-gated and Ca 2+ -dependent K + channels control the membrane potential of human T cells and regulate Ca 2+ 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
more » ... 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 Ca 2+ concentration ([Ca 2+ ] 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 [Ca 2+ ] i by 1-28%. Significant reductions in K + current and [Ca 2+ ] 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 [Ca 2+ ] i in activated T cells thus providing a feedback inhibitory mechanism during T cell activation. response, including Ca 2+ entry into the cell (Kummerow et al., 2009; Mossman et al., 2005; Quintana et al., 2005) . A rise in intracellular Ca 2+ levels ([Ca 2+ ] i ) has been shown to follow immediately after APC stimulation and it is essential for activation of transcription factors and mitogenesis. Although Ca 2+ plays such an important role in the T cell activation process, the mechanisms regulating Ca 2+ signaling upon formation of the IS are not fully understood. Ca 2+ signaling in T cells is generated by Ca 2+ influx through Ca 2+ release activated Ca 2+ (CRAC) channels (Cahalan and Chandy, 2009; Kummerow et al., 2009) . CRAC channels are activated by depletion of the endoplasmic reticulum (ER) Ca 2+ store, which is triggered upon T cell receptor (TCR) stimulation. Briefly, TCR stimulation leads to the release of Ca 2+ from the ER via phospholipase Cγ (PLC-γ) activation and production of inositol-3phosphate (IP3). Once ER Ca 2+ stores are sufficiently depleted, stromal interaction molecule 1 (STIM1) in the ER moves into proximity to, and activates, Orai1 (a pore-forming subunit of the CRAC channel) and Ca 2+ influx begins (Cahalan and Chandy, 2009). As Ca 2+ enters the cell the membrane potential depolarizes, which in turn reduces CRAC current and limits Ca 2+ entry. To counteract the cell depolarization and allow an increase in [Ca 2+ ] i of the appropriate magnitude and duration necessary for T cell activation, K + channels (Kv1.3 and KCa3.1) open allowing K + efflux. Kv1.3 channels are voltage dependent and are activated by membrane depolarization while KCa3.1 channels are activated by an increase in [Ca 2+ ] i . K + channels are differentially expressed in T cell subsets at different activation states with Kv1.3 being the predominant K + conductance in human resting T cells (rT) and activated effector memory (aT EM ) cells while KCa3.1 channels are up-regulated in activated naïve and central memory (aT CM ) cells (Cahalan and Chandy, 2009; Koo et al., 1997) . Although K + channels have been implicated in the etiology and progression of various diseases, their regulation during the activation process is not fully understood. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights We model how extracellular K + accumulation in the immunological synapse affects T cell ionic currents. > Increased extracellular K + can decrease T cell Ca 2+ influx. > The decreased Ca 2+ influx is most prominent in activated T cells.
doi:10.1016/j.jtbi.2012.01.018 pmid:22285786 pmcid:PMC3307848 fatcat:ho7bfbonevgatm5hdjj3j6cxpe