Table 1.

Ion channels in immune cells

Channel	Permeability	Activation	Expression in immune cells	Immune function in vitro and in vivo	Channelopathies and immune disease in human
Calcium
CRAC
ORAI1	Ca²⁺	TCR, BCR, FcR, dectin, chemokine receptors → Ca²⁺ depletion from ER stores → STIM1, STIM2 activation	T cells, B cells, NK cells, macrophages, DCs, neutrophils, ubiquitous	T cells in vitro: proliferation, cytokine production, cytotoxicity, apoptosis, chemotaxis T cells in vivo: immunity to infection (human), Th1/Th17 cell–mediated autoimmunity (EAE, IBD); DTH; skin allograft rejection; motility and homing (?) NK cells: degranulation, cytotoxicity (human) DCs (in vitro cultured): maturation (?), cytokine production (?) Mast cells: degranulation, histamine release, cytokine and LTC₄ production, passive cutaneous analphylaxis Neutrophils: ROS production, adhesion (?)	CRAC channelopathy due to mutations in human ORAI1 (immunodeficiency, autoimmunity, muscular hypotonia, ectodermal dysplasia)
ORAI2	Ca²⁺	Presumably similar to ORAI1	B cells (human); ubiquitous (mouse)	t.b.d.
ORAI3	Ca²⁺	Presumably similar to ORAI1	Ubiquitous (lowest in T cells)	t.b.d.
STIM1, STIM2	NA	ER store depletion	Ubiquitous	Similar to ORAI1. STIM1-deficient mice have attenuated EAE, IBD, GvHD (T cells), reduced cytokine production, FcγR-dependent phagocytosis of antibody-opsonized RBC and platelets (macrophage), reduced ROS and phagocytosis, increased susceptibility to S. aureus and L. monocytogenes? (neutrophils) STIM1/2-deficient mice have impaired development of Foxp3⁺ Treg, NKT, and IEL cells, myelo-lymphoproliferation, inflammation (lung, intestine, salivary glands), impaired antitumor and antiviral immunity, impaired CD8⁺ T cell memory	CRAC channelopathy due to mutations in STIM1 (see ORAI1)
TRP
TRPC3, C5	Ca²⁺,Na⁺	Unknown [(GM1) ganglioside activates TRPC5 (?)]		Unknown
TRPM2	Ca²⁺,Na⁺	ADPR, cADPR, NAADP	T cells, macrophages	Activation and cytokine production by macrophages (and T cells); inflammasome activation; Trpm2⁻^/⁻ mice are susceptible to infection with L. monocytogenes and are resistant to obesity-induced diabetes and DSS-induced colitis
TRPV2	Ca²⁺,Na⁺	FcγR signaling	Macrophages	Chemotaxis and phagocytosis by macrophages; Trpv2⁻^/⁻ mice show increased susceptibility to L. monocytogenes
Ca_V
Ca 1.2, 1.3, V 1.4 (and β3, β4 regulatory subunits)	Ca^{2 +}	Activation mechanism unknown, inhibition by STIM1 (in Jurkat T cells)	T cells	Positive selection of CD4⁺ T cells (?) (Ca_V1.4), CD8⁺ T cell survival, cytokine production, CD8⁺ T cell immunity to L. monocytogenes infection, Th2 function in asthma (Ca_V1.2)
P2X
P2RX7	Ca²⁺,Na⁺, K⁺,other	Extracellular ATP	Ubiquitous	T cell proliferation, cytokine production; promotes Th17 and inhibits Treg differentiation; the pan-P2RX inhibitor oATP prevents IBD, cardiac and pancreatic islet allograft rejection Innate immune cells: NLRP3 inflammasome activation (K⁺ efflux); activation/priming of DCs in CD8⁺ T cell–mediated antitumor immunity and CD4⁺ T cell–mediated GvHD; immunity to M. tuberculosis in mice	Polymorphisms in human gene are associated with increased susceptibility to M. tuberculosis
P2RX1, 2, 3, 4, 5	Ca²⁺,Na⁺	Extracellular ATP	T cells, thymocytes, innate immune cells	T cells: T cell proliferation, cytokine production, thymocyte apoptosis; P2rx2/3⁻^/⁻ mice have hypocellularity of bone marrow and thymus.
Magnesium
TRPM7	Ni²⁺ > Zn²⁺ >Mg²⁺,Ca²⁺	Unknown; regulators include intracellular Mg²⁺,PIP₂, extracellular pH	T, B, NK cells	Thymocyte development, production of thymocyte growth factors, proliferation and survival of DT-40 B cells
MAGT1	Mg²⁺	TCR (activation mechanism unknown)	T, NK cells	CD4⁺ T cell homeostasis, NKG2D expression on CD8⁺ T and NK cells, cytotoxicity, immunity to viral infection (EBV)	XMEN disease (immunodeficiency, CD4 lymphopenia, EBV infections)
Zinc
ZIP3, ZIP6, ZIP8, ZIP10, ZIP14	Zn²⁺	Unknown; TCR stimulation (ZIP6)	T cells, B cells, macrophages, DCs	T cells: activation (ZIP6); IFN-γ and perforin expression (ZIP8); T cell development (ZIP3) (?) B cells: early B cell development, apoptosis, cytokine signaling (ZIP10) Macrophages: inhibition of proinflammatory cytokine production (ZIP8, ZIP14) DCs: inhibition of LPS induced expression of MHC class II and costimulatory molecules (ZIP6)	Mutations in ZIP4 cause acrodermatitis enteropathica with immunodeficiency (due to impaired intestinal Zn²⁺ uptake)
ZnT5	Zn²⁺	Unknown; FcɛRI stimulation (?)	Mast cells	Zn²⁺ efflux; promotes NF-κB activation in mast cells and FcɛRI-dependent DTH
Potassium
K_V1.3	K⁺	Depolarization of V_m	Th17 and T_EM, IgD⁻CD27⁺ class switched memory B and plasma cells, macrophages, DCs	Function: hyperpolarization of V_m; volume regulation. T cells: activation of Th17 and T_EM cells, proliferation, cytokine production, T cell–mediated autoimmunity; inhibition in mice attenuates EAE, autoimmune diabetes, RA, and ACD; Kv1.3⁻^/⁻ mice resistant to EAE and obesity-induced diabetes Macrophages: proliferation, iNOS expression DCs: expression of CD80, CD86, CD40, IL-12; chemotaxis
K_Ca3.1	K⁺	Intracellular Ca²⁺	Th1, Th2, and T_CM, naive and IgD⁺ CD27⁺ memory B cells, macrophages	Function: hyperpolarization of V_m T cells: activation of Th1, Th2, T_CM cells; cytokine production; IBD. Inhibition attenuates IBD (mice), asthma (rodents, sheep), and allograft vasculopathy Macrophages: chemotaxis, infiltration of atherosclerotic plaques
K_2P 3.1, 5.1, 9.1	K⁺	K⁺ leak channels, activated by pH changes, lipids, stretch	T cells	T cell volume regulation, proliferation, cytokine production; attenuation of EAE in K_2P3.1⁻^/⁻ mice
Sodium
TRPM4	Na⁺	Intracellular Ca²⁺	T cells, DCs, macrophages	Depolarization of V_m; inhibits Ca²⁺ influx and cytokine production in macrophages and mast cells; promotes phagocytosis. In Trpm4⁻^/⁻ mice, increases macrophage function and sepsis mortality, increases mast cell function and PCA.
Na_V1.5	Na⁺	Membrane depolarization (?)	Thymocytes	Sustains Ca²⁺ influx; positive selection of CD4⁺ T cells.
Protons, pH
H_V1	H⁺	Reduced intracellular pH	B cells, macrophages, neutrophils	Sustains activation of NAPDH oxidase and ROS production in neutrophils, macrophages, and B cells; Hvcn1⁻^/⁻ mice have reduced ROS production, antibody responses, and neurological damage in stroke
Ae2	Cl⁻/HCO₃⁻		CD8⁺ T cells	CD8⁺ T cells from Ae2⁻^/⁻ mice have intracellular alkalization, increased IL-2 production, and increased proliferation
Chloride
GABA_A	Cl⁻	Extracellular GABA	T cells	Inhibition of T cell proliferation, cytokine production, cytotoxicity, T cell–mediated autoimmunity; inhibition attenuates EAE, CIA, diabetes in rodent models
CFTR	Cl⁻	cAMP	T and B cells	ΔF508 mutation impairs cytokine production by human T cells; Cftr⁻^/⁻ murine T cells show exacerbated IL-4, IL-13 production, and IgE response to Aspergillus fumigatus
LRRC8A (alias: SWELL1), corre-sponding current: VRAC or Cl_swell	Cl⁻ (I⁻,Br⁻)	Hypotonicity-mediated cell swelling	T cells, B cells, probably ubiquitous	Volume regulation; Lrrc8⁻^/⁻ mice have severely impaired T cell development and moderately impaired B cell development	Heterozygous truncation mutation in LRRC8A causes congenital agammaglobulinemia with no circulating B cells

This table summarizes ion channels and transporters whose function in immune cells in vitro and in vivo is supported by genetic evidence (mutations in human patients, knockout mice, RNAi in mammalian cells) or by selective channel inhibitors. Nevertheless, the degree of evidence for a role of the listed channels and transporters in immune function varies greatly, as discussed in the text. Question marks (?) indicate greater level of uncertainty or ambiguous results in different studies. > indicates the selectivity of ion channels/transporters for specific cations. Arrows (→) indicate activating signals.

Abbreviations: ACD, allergic contact dermatitis; ADPR, ADP ribose; Ae2, anion exchanger 2; cADPR, cyclic ADP ribose; cAMP, cyclic adenosine monophosphate; Ca_V, voltage-gated Ca²⁺ channel; CFTR, cystic fibrosis transmembrane conductance regulator; CIA, collagen-induced arthritis; CRAC, Ca²⁺ release–activated Ca²⁺ channel; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; GABA, γ-aminobutyric acid; H_V1, voltage-gated proton channel; IBD, inflammatory bowel disease: GvHD, graft-versus-host disease; IEL, intraepithelial lymphocyte; K_Ca,Ca²⁺-activated K⁺ channel; K_V, voltage-gated K⁺ channel; LPS, lipopolysaccharide; MagT, Mg²⁺ transporter; MHC, major histocompatibility complex; NAADP, nicotinic acid adenine dinucleotide phosphate; NKT, natural killer T cell; PCA, passive cutaneous anaphylaxis; RA, rheumatoid arthritis; ROS, reactive oxygen species; STIM, stromal interaction molecule; t.b.d., to be determined; T_CM, central memory T cell; Treg, regulatory T cell; TRP, transient receptor potential; V_m, membrane potential; XMEN, X-linked immunodeficiency with Mg²⁺ defect and EBV infection and neoplasia; ZIP, Zrt-Irt-like protein; ZnT, zinc transporter.