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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    • "These results suggest that TIM-1 is poised to be exposed on the cell surface after activation under specific conditions and that TIM-1 plays a role in lymphocyte extravasation as an activation-dependent primary adhesion molecule. Moreover, recent data suggest that cells transfected with TIM-1 expose the mucin domain on the cell surface following intracellular calcium release (Santiago et al., 2007b), and a ''flip-flop'' model was proposed in which the TIM-1 extracellular domain resides on the cytosolic side of the membrane, with the IgV domain interacting with phosphatidylserine (Santiago et al., 2007a). However , TIM-1 molecule in Th2 and Treg cells might also not be properly glycosylated, compared to Th1 and Th17 cells, and its differential role as P-selectin rolling receptor might reflect both distribution and glycosylation differences between T cell subsets. "
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    ABSTRACT: Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper 1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but it reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 immunoglobulin variable domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease.
    Immunity 04/2014; 40(4). DOI:10.1016/j.immuni.2014.03.004 · 21.56 Impact Factor
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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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