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Modulation of Kv channel expression and function by TCR and costimulatory signals during peripheral CD4(+) lymphocyte
Qing-Hua Liu1, Bernd K Fleischmann, Brian Hondowicz
1Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Abstract:
Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4(+) lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor-mediated stimulation and costimulatory signals. Currents expressed in naive CD4(+) lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4(+) cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4(+) lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4(+) lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN-gamma production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling.
Insights
Voltage-dependent potassium (Kv) channels are crucial for T cell responses. Different Kv channel expressions in naive, effector, and anergized T cells influence their distinct functions in cytokine production.
Area of Science:
- Immunology
- Cellular Signaling
- Ion Channel Physiology
Background:
- Ionic signaling pathways, particularly voltage-dependent potassium (Kv) channels, play a key role in T cell responses.
- The specific roles of Kv channels in T cell activation, differentiation, and function remain largely uncharacterized.
Purpose of the Study:
- To investigate the expression patterns of Kv channels in naive, effector, and anergized CD4(+) T cells.
- To determine the functional contribution of Kv channels to the distinct activities of these T cell subsets, focusing on cytokine production.
Main Methods:
- Electrophysiological recordings to characterize Kv channel currents in different T cell populations.
- Analysis of Kv channel expression profiles in naive, effector, and anergized CD4(+) lymphocytes.
- Assessment of cytokine production (IL-2, IL-4, IFN-gamma) in relation to Kv channel activity.
Main Results:
- Naive CD4(+) T cells express Kv1.1, Kv1.2, Kv1.3, and Kv1.6 channels, with antigen receptor stimulation modulating current amplitude and kinetics.
- Effector CD4(+) T cells show significantly increased Kv1.3 current, while anergized cells exhibit elevated Kv1.3 and similar Kv1.1, Kv1.2, and/or Kv1.6 currents compared to naive cells.
- Kv channels are essential for IL-2 production in naive T cells, play no role in effector cell cytokine production, and actively suppress IL-4 production in anergized T cells.
Conclusions:
- Kv channel expression and function vary significantly across naive, effector, and anergized CD4(+) T cell states.
- Kv channels are critical regulators of T cell function, influencing cytokine profiles and potentially membrane potential and calcium signaling in a state-dependent manner.