Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway.

Hdl Handle:
http://hdl.handle.net/10147/135799
Title:
Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway.
Authors:
Cao, Wei; Ryan, Michelle; Buckley, Deirdre; O'Connor, Rosemary; Clarkson, Michael R
Affiliation:
Immunology, Moffitt Cancer Center Department of Biochemistry Department of Renal Medicine, Cork University Hospital, University College Cork, Ireland.
Citation:
Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway. 2011, 133 (2):179-89 Immunology
Journal:
Immunology
Issue Date:
Jun-2011
URI:
http://hdl.handle.net/10147/135799
DOI:
10.1111/j.1365-2567.2011.03424.x
PubMed ID:
21463297
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/21463297
Abstract:
Emerging experimental data suggest an important role for the T-cell immunoglobulin mucin 1 (Tim-1):Tim-4 pathway in autoimmune and alloimmune responses in vivo. Using a Tim-4 ectodomain human IgG Fc fusion protein we studied the role of Tim-4 in T-cell activation, signalling and differentiation responses in vitro. We demonstrate that Tim-4Fc can inhibit naive and pre-activated T-cell activation, proliferation and cytokine secretion via a Tim-1-independent pathway. Tim-4 contains immunoglobulin variable (IgV) and mucin domains; to identify which domain accounts for the inhibitory effect novel Tim-4 fusion proteins containing either the IgV or mucin domain were generated. We demonstrate that both IgV and mucin domains are required for the inhibitory effects and that they are mediated at least in part by inhibition of extracellular signal-regulated kinase pathway activity. Given the emerging interest in the role of the Tim family in T helper type 17 (Th17) cells, which play an important role in autoimmune disease and transplantation tolerance, our data show that Tim-4Fc can prevent polarization of CD4(+) T cells to the Th17 phenotype. Collectively, our results highlight an inhibitory role for Tim-4Fc in vitro, which we propose is mediated by a receptor other than Tim-1. In addition, this study provides new insights into the role of Tim-4Fc in regulating Th17 immune responses and may open a new avenue for autoimmune therapy.
Item Type:
Article
Language:
en
MeSH:
Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Cells, Cultured; Enzyme Activation; Humans; Immunoglobulin G; Immunoglobulin Variable Region; Lymphocyte Activation; Membrane Proteins; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Mucins; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins; STAT3 Transcription Factor; Signal Transduction; Th17 Cells
ISSN:
1365-2567

Full metadata record

DC FieldValue Language
dc.contributor.authorCao, Weien
dc.contributor.authorRyan, Michelleen
dc.contributor.authorBuckley, Deirdreen
dc.contributor.authorO'Connor, Rosemaryen
dc.contributor.authorClarkson, Michael Ren
dc.date.accessioned2011-07-11T13:25:15Z-
dc.date.available2011-07-11T13:25:15Z-
dc.date.issued2011-06-
dc.identifier.citationTim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway. 2011, 133 (2):179-89 Immunologyen
dc.identifier.issn1365-2567-
dc.identifier.pmid21463297-
dc.identifier.doi10.1111/j.1365-2567.2011.03424.x-
dc.identifier.urihttp://hdl.handle.net/10147/135799-
dc.description.abstractEmerging experimental data suggest an important role for the T-cell immunoglobulin mucin 1 (Tim-1):Tim-4 pathway in autoimmune and alloimmune responses in vivo. Using a Tim-4 ectodomain human IgG Fc fusion protein we studied the role of Tim-4 in T-cell activation, signalling and differentiation responses in vitro. We demonstrate that Tim-4Fc can inhibit naive and pre-activated T-cell activation, proliferation and cytokine secretion via a Tim-1-independent pathway. Tim-4 contains immunoglobulin variable (IgV) and mucin domains; to identify which domain accounts for the inhibitory effect novel Tim-4 fusion proteins containing either the IgV or mucin domain were generated. We demonstrate that both IgV and mucin domains are required for the inhibitory effects and that they are mediated at least in part by inhibition of extracellular signal-regulated kinase pathway activity. Given the emerging interest in the role of the Tim family in T helper type 17 (Th17) cells, which play an important role in autoimmune disease and transplantation tolerance, our data show that Tim-4Fc can prevent polarization of CD4(+) T cells to the Th17 phenotype. Collectively, our results highlight an inhibitory role for Tim-4Fc in vitro, which we propose is mediated by a receptor other than Tim-1. In addition, this study provides new insights into the role of Tim-4Fc in regulating Th17 immune responses and may open a new avenue for autoimmune therapy.-
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/21463297en
dc.subject.meshAnimals-
dc.subject.meshCD4-Positive T-Lymphocytes-
dc.subject.meshCell Differentiation-
dc.subject.meshCell Proliferation-
dc.subject.meshCells, Cultured-
dc.subject.meshEnzyme Activation-
dc.subject.meshHumans-
dc.subject.meshImmunoglobulin G-
dc.subject.meshImmunoglobulin Variable Region-
dc.subject.meshLymphocyte Activation-
dc.subject.meshMembrane Proteins-
dc.subject.meshMice-
dc.subject.meshMice, Inbred BALB C-
dc.subject.meshMitogen-Activated Protein Kinases-
dc.subject.meshMucins-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshRecombinant Proteins-
dc.subject.meshSTAT3 Transcription Factor-
dc.subject.meshSignal Transduction-
dc.subject.meshTh17 Cells-
dc.titleTim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway.en
dc.typeArticleen
dc.contributor.departmentImmunology, Moffitt Cancer Center Department of Biochemistry Department of Renal Medicine, Cork University Hospital, University College Cork, Ireland.en
dc.identifier.journalImmunologyen
dc.description.provinceMunster-

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