Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis

Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K(+) channel, is a functional marker and a pharmacological target for activated effector memory T cells. Selective Kv1.3 blockers have been shown to inhibit prol...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2012-06, Vol.188 (12), p.5877-5886
Main Authors: Gocke, Anne R, Lebson, Lori A, Grishkan, Inna V, Hu, Lina, Nguyen, Hai M, Whartenby, Katharine A, Chandy, K George, Calabresi, Peter A
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
CD4-Positive T-Lymphocytes - cytology
CD4-Positive T-Lymphocytes - immunology
Cell Differentiation - immunology
Electrophysiology
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - metabolism
Encephalomyelitis, Autoimmune, Experimental - pathology
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Kv1.3 Potassium Channel - metabolism
Lymphocyte Activation - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phenotype
T-Lymphocyte Subsets - cytology
T-Lymphocyte Subsets - immunology
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K(+) channel, is a functional marker and a pharmacological target for activated effector memory T cells. Selective Kv1.3 blockers have been shown to inhibit proliferation and cytokine production by human and rat effector memory T cells. We used Kv1.3 knockout (KO) mice to investigate the mechanism by which Kv1.3 blockade affects CD4(+) T cell differentiation during an inflammatory immune-mediated disease. Kv1.3 KO animals displayed significantly lower incidence and severity of myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis. Kv1.3 was the only K(V) channel expressed in MOG 35-55-specific CD4(+) T cell blasts, and no K(V) current was present in MOG-specific CD4(+) T cell-blasts from Kv1.3 KO mice. Fewer CD4(+) T cells migrated to the CNS in Kv1.3 KO mice following disease induction, and Ag-specific proliferation of CD4(+) T cells from these mice was impaired with a corresponding cell-cycle delay. Kv1.3 was required for optimal expression of IFN-γ and IL-17, whereas its absence led to increased IL-10 production. Dendritic cells from Kv1.3 KO mice fully activated wild-type CD4(+) T cells, indicating a T cell-intrinsic defect in Kv1.3 KO mice. The loss of Kv1.3 led to a suppressive phenotype, which may contribute to the mechanism by which deletion of Kv1.3 produces an immunotherapeutic effect. Skewing of CD4(+) T cell differentiation toward Ag-specific regulatory T cells by pharmacological blockade or genetic suppression of Kv1.3 might be beneficial for therapy of immune-mediated diseases such as multiple sclerosis.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1103095