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- Publisher Website: 10.4049/jimmunol.1103095
- Scopus: eid_2-s2.0-84862590535
- PMID: 22581856
- WOS: WOS:000305077900012
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Article: Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis
Title | Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis |
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Authors | |
Issue Date | 2012 |
Citation | Journal of Immunology, 2012, v. 188, n. 12, p. 5877-5886 How to Cite? |
Abstract | 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 KV channel expressed in MOG 35-55-specific CD4 + T cell blasts, and no KV 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. Copyright © 2012 by The American Association of Immunologists, Inc. |
Persistent Identifier | http://hdl.handle.net/10722/237106 |
ISSN | 2023 Impact Factor: 3.6 2023 SCImago Journal Rankings: 1.558 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Gocke, Anne R. | - |
dc.contributor.author | Lebson, Lori A. | - |
dc.contributor.author | Grishkan, Inna V. | - |
dc.contributor.author | Hu, Lina | - |
dc.contributor.author | Nguyen, Hai M. | - |
dc.contributor.author | Whartenby, Katharine A. | - |
dc.contributor.author | Chandy, K. George | - |
dc.contributor.author | Calabresi, Peter A. | - |
dc.date.accessioned | 2016-12-20T06:48:38Z | - |
dc.date.available | 2016-12-20T06:48:38Z | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | Journal of Immunology, 2012, v. 188, n. 12, p. 5877-5886 | - |
dc.identifier.issn | 0022-1767 | - |
dc.identifier.uri | http://hdl.handle.net/10722/237106 | - |
dc.description.abstract | 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 KV channel expressed in MOG 35-55-specific CD4 + T cell blasts, and no KV 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. Copyright © 2012 by The American Association of Immunologists, Inc. | - |
dc.language | eng | - |
dc.relation.ispartof | Journal of Immunology | - |
dc.title | Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.4049/jimmunol.1103095 | - |
dc.identifier.pmid | 22581856 | - |
dc.identifier.scopus | eid_2-s2.0-84862590535 | - |
dc.identifier.volume | 188 | - |
dc.identifier.issue | 12 | - |
dc.identifier.spage | 5877 | - |
dc.identifier.epage | 5886 | - |
dc.identifier.eissn | 1550-6606 | - |
dc.identifier.isi | WOS:000305077900012 | - |
dc.identifier.issnl | 0022-1767 | - |