Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.
Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.
Beeton
Christine
C
Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
Wulff
Heike
H
Standifer
Nathan E
NE
Azam
Philippe
P
Mullen
Katherine M
KM
Pennington
Michael W
MW
Kolski-Andreaco
Aaron
A
Wei
Eric
E
Grino
Alexandra
A
Counts
Debra R
DR
Wang
Ping H
PH
LeeHealey
Christine J
CJ
S Andrews
Brian
B
Sankaranarayanan
Ananthakrishnan
A
Homerick
Daniel
D
Roeck
Werner W
WW
Tehranzadeh
Jamshid
J
Stanhope
Kimber L
KL
Zimin
Pavel
P
Havel
Peter J
PJ
Griffey
Stephen
S
Knaus
Hans-Guenther
HG
Nepom
Gerald T
GT
Gutman
George A
GA
Calabresi
Peter A
PA
Chandy
K George
KG
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
C515370:CCR7 protein, human; C515372:Ccr7 protein, rat; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human; D054400:Receptors, CCR7; D019707:Receptors, Chemokine