The role of ion channels in T cell function and disease

Abstract

T lymphocytes (T cells) are an important sub-group of cells in our immune system responsible for cell-mediated adaptive responses and maintaining immune homeostasis. Abnormalities in T cell function, lead the way to the persistence of infection, impaired immunosurveillance, lack of suppression of cancer growth, and autoimmune diseases. Ion channels play a critical role in the regulation of T cell signaling and cellular function and are often overlooked and understudied. Little is known about the ion "channelome" and the interaction of ion channels in immune cells. This review aims to summarize the published data on the impact of ion channels on T cell function and disease. The importance of ion channels in health and disease plus the fact they are easily accessible by virtue of being expressed on the surface of plasma membranes makes them excellent drug targets.

Keywords: T cells; antigen receptor; calcium signalling; ion channels; signal transduction; therapeutics.

Figure 1

Ion channels and transporters showing the flow of cations and anions in T cells. Abbreviations. CFTR—cystic fibrosis transmembrane conductance regulator, CRAC—Ca²⁺ release-activated channel, GABA—γ-amino butyric acid, P2X—purinergic receptor, T—T cell, TRP—transient receptor potential family, leucine-rich repeat-containing 8 protein (LRRC8) receptors eg LRRCBA. N-methyl-D- aspartate (NMDA); Magnesium transporter protein 1 (MAGT1); Voltage-gated proton channels (Hvcn1); TRP mulcolipin (TRPM), ZIP 6, zinc transporter.

Figure 2

Overview of transcriptional events following TCR signal transduction. T cell activation results in signal propagation via three major signalling pathways: the Ca²⁺–calcineurin, mitogen-activated protein kinase (MAPK), and NF-κB signalling pathways. The concerted activity of these pathways, lead to the activation of transcription factors (Jun, Fos, AP-1, NF-κB, NFAT) that results in T cell proliferation, migration, cytokine production and effector functions. Abbreviation: phosphatidylinositol 3-kinase (PI3K), CRAC, Ca²⁺ release-activated Ca²⁺ channel; DAG, diacylglycerol; ER, endoplasmic reticulum; InsP3, inositol trisphosphate; JNK, Jun N-terminal kinase; PLCγ1, phospholipase Cγ1; PtdIns(4,5)P2, phosphatidylinositol 4,5-bisphosphate.