Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block.
Effector memory T (Tem) cells are essential mediators of autoimmune disease and delayed-type hypersensitivity (DTH), a convenient model for two-photon imaging of Tem cell participation in an inflammatory response. Shortly (3 hr) after entry into antigen-primed ear tissue, Tem cells stably attached to antigen-bearing antigen-presenting cells (APCs). After 24 hr, enlarged Tem cells were highly motile along collagen fibers and continued to migrate rapidly for 18 hr. Tem cells rely on voltage-gated Kv1.3 potassium channels to regulate calcium signaling. ShK-186, a specific Kv1.3 blocker, inhibited DTH and suppressed Tem cell enlargement and motility in inflamed tissue but had no effect on homing to or motility in lymph nodes of naive and central memory T (Tcm) cells. ShK-186 effectively treated disease in a rat model of multiple sclerosis. These results demonstrate a requirement for Kv1.3 channels in Tem cells during an inflammatory immune response in peripheral tissues. Targeting Kv1.3 allows for effector memory responses to be suppressed while central memory responses remain intact.
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697-4561, USA.
Melanie P
MP
Matheu
Christine
C
Beeton
Adriana
A
Garcia
Victor
V
Chi
Srikant
S
Rangaraju
Olga
O
Safrina
Kevin
K
Monaghan
Marc I
MI
Uemura
Dan
D
Li
Sukumar
S
Pal
Luis M
LM
de la Maza
Edwin
E
Monuki
Alexander
A
Flügel
Michael W
MW
Pennington
Ian
I
Parker
K George
KG
Chandy
Michael D
MD
Cahalan
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002690:Chlamydia Infections / Q000188:drug therapy / Q000276:immunology; D002692:Chlamydia trachomatis / Q000276:immunology; D003094:Collagen; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D054400:Receptors, CCR7 / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
C515372:Ccr7 protein, rat; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D011506:Proteins; D054400:Receptors, CCR7; C533637:Shk-186 peptide; D010047:Ovalbumin; D003094:Collagen