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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...
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| Published in: | The Journal of immunology (1950) 2012-06, Vol.188 (12), p.5877-5886 |
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| Main Authors: | , , , , , , , |
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| cited_by | cdi_FETCH-LOGICAL-c374t-b79f89a91dbeb8ee77fbaf762c478e9860af3f4d1566c00578510805fe2aff323 |
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| cites | cdi_FETCH-LOGICAL-c374t-b79f89a91dbeb8ee77fbaf762c478e9860af3f4d1566c00578510805fe2aff323 |
| container_end_page | 5886 |
| container_issue | 12 |
| container_start_page | 5877 |
| container_title | The Journal of immunology (1950) |
| container_volume | 188 |
| creator | Gocke, Anne R Lebson, Lori A Grishkan, Inna V Hu, Lina Nguyen, Hai M Whartenby, Katharine A Chandy, K George Calabresi, Peter A |
| description | 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. |
| doi_str_mv | 10.4049/jimmunol.1103095 |
| format | article |
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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. 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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.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>CD4-Positive T-Lymphocytes - cytology</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cell Differentiation - immunology</subject><subject>Electrophysiology</subject><subject>Encephalomyelitis, Autoimmune, Experimental - immunology</subject><subject>Encephalomyelitis, Autoimmune, Experimental - metabolism</subject><subject>Encephalomyelitis, Autoimmune, Experimental - pathology</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Kv1.3 Potassium Channel - metabolism</subject><subject>Lymphocyte Activation - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Phenotype</subject><subject>T-Lymphocyte Subsets - cytology</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocytes, Regulatory - cytology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNqFkb1PwzAQxS0EgvKxMyGPLClnJ7aTEVV8CSQWmCMnOVOjJA62A-rA_05KW1am0-l-753uHiHnDOYZZMXVu-26sXftnDFIoRB7ZMaEgERKkPtkBsB5wpRUR-Q4hHcAkMCzQ3LEuchZLuSMfD9-snlKG2wxWtfTyuqAgb7QGts20Oi-tG-o7ulmk8e3sdXR-RUdlti7uBpwmjbUY9-gD7SzNU5NsCHqPk56qsfofsVIsa9xWOrWdStsbbThlBwY3QY829YT8np787K4T56e7x4W109JnaosJpUqTF7ogjUVVjmiUqbSRkleZyrHIpegTWqyhgkpawChcsEgB2GQa2NSnp6Qy43v4N3HiCGWnQ3rC3WPbgzl9DQmmVI8_R8FVsiJz2BCYYPW3oXg0ZSDt532qwkq1_mUu3zKbT6T5GLrPlYdNn-CXSDpD74LkDw</recordid><startdate>20120615</startdate><enddate>20120615</enddate><creator>Gocke, Anne R</creator><creator>Lebson, Lori A</creator><creator>Grishkan, Inna V</creator><creator>Hu, Lina</creator><creator>Nguyen, Hai M</creator><creator>Whartenby, Katharine A</creator><creator>Chandy, K George</creator><creator>Calabresi, Peter A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope></search><sort><creationdate>20120615</creationdate><title>Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis</title><author>Gocke, Anne R ; 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| ispartof | The Journal of immunology (1950), 2012-06, Vol.188 (12), p.5877-5886 |
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| 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 |
| title | Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis |
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