The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain.
Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (T(EM)) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3(+) T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7(-)), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7(+) central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7(-) T(EM), suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T(EM). These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.
Rus
Horea
H
Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Pardo
Carlos A
CA
Hu
Lina
L
Darrah
Erika
E
Cudrici
Cornelia
C
Niculescu
Teodora
T
Niculescu
Florin
F
Mullen
Katharine M
KM
Allie
Rameeza
R
Guo
Liping
L
Wulff
Heike
H
Beeton
Christine
C
Judge
Susan I V
SI
Kerr
Douglas A
DA
Knaus
Hans-Gunther
HG
Chandy
K George
KG
Calabresi
Peter A
PA
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051664:Kv1.3 Potassium Channel; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
C515370:CCR7 protein, human; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D054400:Receptors, CCR7; D019707:Receptors, Chemokine