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.
Affiliation
Immunology, Moffitt Cancer Center Department of Biochemistry Department of Renal Medicine, Cork University Hospital, University College Cork, Ireland.Issue Date
2011-06MeSH
AnimalsCD4-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
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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 ImmunologyJournal
ImmunologyDOI
10.1111/j.1365-2567.2011.03424.xPubMed ID
21463297Additional Links
http://www.ncbi.nlm.nih.gov/pubmed/21463297Abstract
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
ArticleLanguage
enISSN
1365-2567ae974a485f413a2113503eed53cd6c53
10.1111/j.1365-2567.2011.03424.x
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