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Currently available immunotherapies have improved the treatment of autoimmune diseases; however, these therapies are known to have considerable side-effects, such as increasing the susceptibility to infections. Therefore, there is an unmet need for novel immunosuppressive strategies with different mechanisms of action and higher specificity for disease-causing autoreactive T lymphocytes from existing immunomodulators.  The increase of the cytoplasmic calcium concentration from intra- and extracellular sources (i.e., the endoplasmic reticulum and store-operated calcium entry through the plasma membrane) is the cornerstone of T lymphocyte activation and functionality. In the course of lymphocyte activation, potassium channels maintain the driving force for sustained calcium influx from the extracellular milieu as they grant the efflux of potassium from the cytoplasm, thus conserving an electrochemical potential gradient between the intra- and extracellular spaces. There are two major types of potassium channels in T cells: the voltage-gated Kv1.3 and the calcium-activated IKCa1 channels. The relation between the calcium currents through calcium release-activated calcium (CRAC) channels and the efflux of potassium makes the proliferation and activation of lymphocytes sensitive to pharmacological modulation of Kv1.3 and IKCa1 channels, and provides an opportunity for targeted intervention. Specific inhibition of these channels results in a diminished calcium influx in lymphocytes and a lower level of lymphocyte activation.  Previous data suggest that selective modulation of lymphocyte activation through specific inhibition of potassium channels may be a possible therapeutic approach for the treatment of autoimmune disease (1–,6). Beeton et al. showed that terminally differentiated effector memory T (TEM) cells play a pivotal role in the pathogenesis of autoimmunity (4). Wulff et al. described that the characteristic potassium channel phenotype of TEM cells in multiple sclerosis (MS) is Kv1.3high IKCa1low, contrasting naive, and central memory T (TCM) cells, which exhibit a Kv1.3low IKCa1high channel phenotype (1). Therefore the therapeutic relevance of specific Kv1.3 channel inhibitors is of outstanding interest, as they may offer the possibility for selective modulation of pathogenic TEM cells, while naive and TCM cells (needed for physiological immune responses) would escape the inhibition through upregulation of IKCa1 channel expression. Beeton et al. demonstrated that the symptoms of experimental autoimmune encephalitis, a murine model of MS, significantly improved after treatment with selective Kv1.3 inhibitors (5).  Although results from animal models are promising, limited data is available on the effects of potassium channel inhibition on T cell function in humans. Furthermore, besides naive and memory T cells, alterations in the activation pattern of effector (CD4+ helper and CD8+ cytotoxic) T lymphocytes have not been described upon Kv1.3 and IKCa1 inhibition. Although these cells might have a less-specific role in the maintenance of autoreactivity compared to TEM cells, their inhibition have important consequences on the overall immune response. Therefore, over the recent years, we have investigated calcium influx characteristics in effector T cell subsets in a number of autoimmune disorders.  We isolated peripheral blood mononuclear cells from MS, rheumatoid arthritis (RA) and type 1 diabetes mellitus (T1DM) patients and applied a novel flow cytometry-based approach for the detection of calcium influx (7–10). Until the recent past, single-cell techniques were used for the investigation of calcium influx during lymphocyte activation. There has been no high-throughput method available to study the kinetics of lymphocyte activation in more subsets at the same time. Single-cell techniques are restricted by not being capable of characterizing this process in complex cellular systems, thus ignoring the interaction between the different lymphocyte subsets that may modulate the course of their activation. Therefore, over the recent years we have developed a novel algorithm that allows simultaneous monitoring of calcium influx in several lymphocyte subsets. Our software (FacsKin) fits functions to median values of the data of interest and calculates relevant parameters describing each function. By selecting the best fitting function, this approach provides an opportunity for the mathematical analysis and statistical comparison of kinetic flow cytometry measurements of distinct samples (more details available at www.facskin.com). Our findings indicate important differences in calcium influx kinetics in the studied autoimmune disorders compared to healthy controls.

Modulation of T Lymphocyte Calcium Influx Patterns Via the Inhibition of Kv1.3 and Ikca1 Potassium Channels in Autoimmune Disorders