Structures of T Cell Immunoglobulin Mucin Receptors 1 and 2 Reveal Mechanisms for Regulation of Immune Responses by the TIM Receptor Family

Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain.
Immunity (Impact Factor: 21.56). 04/2007; 26(3):299-310. DOI: 10.1016/j.immuni.2007.01.014
Source: PubMed


The T cell immunoglobulin mucin (TIM) receptors are involved in the regulation of immune responses, autoimmunity, and allergy. Structures of the N-terminal ligand binding domain of the murine mTIM-1 and mTIM-2 receptors revealed an immunoglobulin (Ig) fold, with four Cys residues bridging a distinctive CC' loop to the GFC beta-sheet. The structures showed two ligand-recognition modes in the TIM family. The mTIM-1 structure identified a homophilic TIM-TIM adhesion interaction, whereas the mTIM-2 domain formed a dimer that prevented homophilic binding. Biochemical, mutational, and cell adhesion analyses confirmed the divergent ligand-binding modes revealed by the structures. Structural features characteristic of mTIM-1 appear conserved in human TIM-1, which also mediated homophilic interactions. The extracellular mucin domain enhanced binding through the Ig domain, modulating TIM receptor functions. These results explain the divergent immune functions described for the murine receptors and the role of TIM-1 as a cell adhesion receptor in renal regeneration and cancer.

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Available from: Angela Ballesteros Morcillo, Aug 12, 2015
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    • "We find that Tim-1 is found mostly on the cell surface of T cells in the steady state. This is in contrast to previously published reports suggesting that Tim-1 is maintained in a mostly intracellular store and only becomes localized to the cell surface upon activation 37. These discrepancies could be due to differences in cell type. "
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    ABSTRACT: The interaction between T cells and APCs bearing cognate antigen results in the formation of an immunological synapse (IS). During this process, many receptors and signaling proteins segregate to regions proximal to the synapse. This protein movement is thought to influence T cell function. However, some proteins are transported away from the IS, which is controlled in part by ERM family proteins. Tim-1 is a transmembrane protein with co-stimulatory functions that is found on many immune cells, including T cells. However, the expression pattern of Tim-1 on T cells upon activation by APCs has not been explored. Interestingly, in this study we demonstrate that the majority of Tim-1 on activated T cells is excluded from the IS. Tim-1 predominantly resides outside of the IS, and structure/function studies indicate that the cytoplasmic tail influences Tim-1 polarization. Specifically, a putative ERM binding motif (KRK 244-246) in the Tim-1 cytoplasmic tail appears necessary for proper Tim-1 localization. Furthermore, mutation of the KRK motif results in enhanced Tim1-mediated early tyrosine phosphorylation downstream of TCR/CD28 stimulation. Paradoxically however, the KRK motif is necessary for Tim-1 induced NFAT/AP-1 activation and co-stimulation of cytokine production. This work reveals unexpected complexity underlying Tim-1 localization and suggests potentially novel mechanisms by which Tim-1 modulates T cell activity.
    F1000 Research 10/2012; 1:10. DOI:10.12688/f1000research.1-10.v1
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    • "Human TIM IgV-like domains share 40% homology and are cysteine rich, suggestive of a highly cross-linked structure.17 In contrast, the mucin-domain presents in an extended conformation. "
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    ABSTRACT: T cell immunoglobulin and mucin-domain (TIM)-containing molecules have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. Despite the initial discovery linking TIM-containing molecules and the airway hyperreactivity regulatory locus in mice, there is a paucity of studies on the function of TIM-containing molecules in lung inflammatory disease. Initially, studies were limited to mice models of asthma. More recently however, TIM-containing molecules have been implicated in an ever-expanding list of airway conditions that includes pneumonia, tuberculosis, influenza, sarcoidosis, lung cancer, and cystic fibrosis. This present review discusses the role of TIM-containing molecules and their ligands in the lung, as well as their potential as therapeutic targets in airway disease.
    Journal of Inflammation Research 08/2012; 5(1):77-87. DOI:10.2147/JIR.S34225
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    • "a chromosomal region that has been shown linked with asthma, allergy, and other autoimmune disorders [43]–[44]. All TIM-family proteins share a common architecture in which the extracellular region possesses a membrane-distal IgV domain and a membrane-proximal mucin domain [45]–[47]. Tim-3 plays an important role in the immune regulation of autoimmune diseases as well as viral infections and has been described as a bi-modal immune regulator in different disease scenarios [48]. In autoimmunity, loss of Tim-3 leads to excessive expansion of auto-reactive T cells [5], [49]. "
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    ABSTRACT: T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a newly identified negative immunomodulator that is up-regulated on dysfunctional T cells during viral infections. The expression and function of Tim-3 on human innate immune responses during HCV infection, however, remains poorly characterized. In this study, we report that Tim-3 is constitutively expressed on human resting CD14(+) monocyte/macrophages (M/M(Ø)) and functions as a cap to block IL-12, a key pro-inflammatory cytokine linking innate and adaptive immune responses. Tim-3 expression is significantly reduced and IL-12 expression increased upon stimulation with Toll-like receptor 4 (TLR4) ligand--lipopolysaccharide (LPS) and TLR7/8 ligand--R848. Notably, Tim-3 is over-expressed on un-stimulated as well as TLR-stimulated M/M(Ø), which is inversely associated with the diminished IL-12 expression in chronically HCV-infected individuals when compared to healthy subjects. Up-regulation of Tim-3 and inhibition of IL-12 are also observed in M/M(Ø) incubated with HCV-expressing hepatocytes, as well as in primary M/M(Ø) or monocytic THP-1 cells incubated with HCV core protein, an effect that mimics the function of complement C1q and is reversible by blocking the HCV core/gC1qR interaction. Importantly, blockade of Tim-3 signaling significantly rescues HCV-mediated inhibition of IL-12, which is primarily expressed by Tim-3 negative M/M(Ø). Tim-3 blockade reduces HCV core-mediated expression of the negative immunoregulators PD-1 and SOCS-1 and increases STAT-1 phosphorylation. Conversely, blocking PD-1 or silencing SOCS-1 gene expression also decreases Tim-3 expression and enhances IL-12 secretion and STAT-1 phosphorylation. These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection.
    PLoS ONE 05/2011; 6(5):e19664. DOI:10.1371/journal.pone.0019664 · 3.23 Impact Factor
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