TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions.
Two major K(+) channels are expressed in T cells, (i) the voltage-dependent K(V)1.3 channel and (ii) the Ca(2+)-activated K(+) channel KCa 3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K(+) conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3(+) T cells revealed a dose-dependent reduction ( approximately 40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pretreatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K(2)P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.
Meuth
Sven G
SG
Department of Neurology, University of Wuerzburg, Wuerzburg, Germany. meuth_s@klinik.uni-wuerzburg.de
Bittner
Stefan
S
Meuth
Patrick
P
Simon
Ole J
OJ
Budde
Thomas
T
Wiendl
Heinz
H
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019295:Computational Biology; D004195:Disease Models, Animal; D004594:Electrophysiology; D004679:Encephalomyelitis / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
D007376:Interleukin-2; C498655:KCNK9 protein, human; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D007371:Interferon-gamma; D011188:Potassium