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.
AffiliationImmunology, Moffitt Cancer Center Department of Biochemistry Department of Renal Medicine, Cork University Hospital, University College Cork, Ireland.
Immunoglobulin Variable Region
Mice, Inbred BALB C
Mitogen-Activated Protein Kinases
Protein Structure, Tertiary
STAT3 Transcription Factor
MetadataShow full item record
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 Immunology
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.
- Anti-T cell immunoglobulin and mucin domain-2 monoclonal antibody exacerbates collagen-induced arthritis by stimulating B cells.
- Authors: Kawamoto T, Abe Y, Ito J, Makino F, Kojima Y, Usui Y, Ma J, Morimoto S, Yagita H, Okumura K, Takasaki Y, Akiba H
- Issue date: 2011 Mar 22
- IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state.
- Authors: Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, Aono H, Ishihara K, Huseby E, Betz UA, Murakami M, Hirano T
- Issue date: 2007 Jun
- Tim-3 ligand galectin-9 reduces IL-17 level and accelerates Klebsiella pneumoniae infection.
- Authors: Wang F, Xu J, Liao Y, Wang Y, Liu C, Zhu X, Chen ZK, Sun Z
- Issue date: 2011
- Suppression of allograft rejection by Tim-1-Fc through cross-linking with a novel Tim-1 binding partner on T cells.
- Authors: Xiao L, Fu ZR, Liu F, Zhang LD, Shi XM, Shen XY, Ni ZJ, Fu H, Li RD, Cao XT, Ding GS, Wang QX
- Issue date: 2011
- Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.
- Authors: Nozaki Y, Nikolic-Paterson DJ, Snelgrove SL, Akiba H, Yagita H, Holdsworth SR, Kitching AR
- Issue date: 2012 May