Статті в журналах: "Mucin domain 1 (TIM-1)"

1

Phong, Binh, and Lawrence P. Kane. "Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies." F1000Research 5 (March 1, 2016): 251. http://dx.doi.org/10.12688/f1000research.8132.1.

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Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

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2

Phong, Binh, and Lawrence P. Kane. "Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies." F1000Research 5 (July 8, 2016): 251. http://dx.doi.org/10.12688/f1000research.8132.2.

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Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

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3

Douna, Hidde, Virginia Smit, Gijs H. M. van Puijvelde, Mate G. Kiss, Christoph J. Binder, llze Bot, Vijay K. Kuchroo, Andrew H. Lichtman, Johan Kuiper, and Amanda C. Foks. "Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis." Atherosclerosis 352 (July 2022): 1–9. http://dx.doi.org/10.1016/j.atherosclerosis.2022.05.017.

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4

Douna, H., V. Smit, G. Puijvelde van, C. Binder, I. Bot, V. Kuchroo, A. Lichtman, J. Kuiper, and A. Foks. "Tim-1 Mucin Domain-Mutant Mice Display Exacerbated Atherosclerosis." Atherosclerosis 287 (August 2019): e25-e26. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.074.

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5

Du, Peng, Ruihua Xiong, Xiaodong Li, and Jingting Jiang. "Immune Regulation and Antitumor Effect of TIM-1." Journal of Immunology Research 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/8605134.

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T cells play an important role in antitumor immunity, and the T cell immunoglobulin domain and the mucin domain protein-1 (TIM-1) on its surface, as a costimulatory molecule, has a strong regulatory effect on T cells. TIM-1 can regulate and enhance type 1 immune response of tumor association. Therefore, TIM-1 costimulatory pathways may be a promising therapeutic target in future tumor immunotherapy. This review describes the immune regulation and antitumor effect of TIM-1.

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6

Jones, Jennifer, Andrew Brandmaier, Sarah Umetsu, Xia Bu, Dale Umetsu, Rosemarie DeKruyff, and Gordon Freeman. "Evolutionary origins and structural analysis of phosphatidylserine binding by the TIM gene family (CAM5P.244)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 180.15. http://dx.doi.org/10.4049/jimmunol.192.supp.180.15.

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Abstract The T cell Immunoglobulin and Mucin-like domain (TIM) proteins are a family of receptors that bind phosphatidylserine (PS) and regulate adaptive and innate immune cell functions. We find that two TIM-specific motifs: a G(W/L/I/F)(F/M)ND (GWFNDor) sequence and four conserved cysteine residues in the FG and CC’ segments of the TIM IgV domain form the distinctive PS-binding pocket identified in TIM-PS co-crystal structures. Because BALB/c and C57BL/6 mice have significant polymorphisms in TIM-3 and TIM-1, we determined the haplotypes of immunologically diverse and genetically divergent mice. Despite a high degree of variation in the IgV domain and in the mucin like stalk, the GWFNDor motif is unmodified in all known polymorphisms of TIM-1, -3, and 4. We identified two genomic alterations that cause divergent expression profiles of TIM-1 in commonly studied mouse strains. A major polymorphism in mouse TIM-1 deletes 23 amino acids of the mucin domain, and is caused by a retroviral insertion in the C57BL/6 genome that prevents expression of part of the mucin domain. Genomic and phylogenetic analyses show that a sytenic locus encoding generally 3 TIMs (1, 3, and 4) is conserved from bony fish to primates, and with emergence of the GWFND-4 motif in the most primitive TIM loci in bony fish, and the TIM family occupies a distinct PS-binding branch among the family of V-domain receptors that modulate immune activation via lipid, glycan, or protein binding.

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7

Curtiss, Miranda L., Bruce S. Hostager, Elizabeth Stepniak, Melody Singh, Natalie Manhica, Judit Knisz, Geri Traver, Paul D. Rennert, John D. Colgan, and Paul B. Rothman. "Fyn binds to and phosphorylates T cell immunoglobulin and mucin domain-1 (Tim-1)." Molecular Immunology 48, no. 12-13 (July 2011): 1424–31. http://dx.doi.org/10.1016/j.molimm.2011.03.023.

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8

Song, Lu, Jiangming Sun, Martin Söderholm, Olle Melander, Marju Orho-Melander, Jan Nilsson, Yan Borné, and Gunnar Engström. "Association of TIM-1 (T-Cell Immunoglobulin and Mucin Domain 1) With Incidence of Stroke." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 7 (July 2020): 1777–86. http://dx.doi.org/10.1161/atvbaha.120.314269.

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9

Kirui, Jared, Yara Abidine, Annasara Lenman, Koushikul Islam, Yong-Dae Gwon, Lisa Lasswitz, Magnus Evander, Marta Bally, and Gisa Gerold. "The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry." Cells 10, no. 7 (July 20, 2021): 1828. http://dx.doi.org/10.3390/cells10071828.

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Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

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10

Phong, Binh, and Lawrence Kane. "Modulation of mast cell function by TIM-1 signaling (177.4)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 177.4. http://dx.doi.org/10.4049/jimmunol.188.supp.177.4.

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Abstract Transmembrane, immunoglobulin and mucin domain (TIM)-1 belongs to a family of transmembrane proteins with emerging roles in immune modulation. As a putative atopy susceptibility gene, polymorphisms in human and mouse TIM-1 are associated with atopic diseases, including asthma and atopic dermatitis. Antibodies targeting different extracellular domains of Tim-1 either attenuated or exacerbated airway inflammation in a mouse model of asthma. Recent studies found that Tim-1 is expressed on mast cells. Tim-1 crosslinking by its ligand Tim-4 enhanced secretion of pro-inflammatory cytokines in IgE and Ag-activated bone marrow-derived mast cells (BMMCs). However, the mechanism(s) by which Tim-1 modulates mast cell function and how Tim-1 activity may be altered by antibody treatment is unknown. We hypothesize that Tim-1 engagement provides a co-stimulatory signal to enhance mast cell degranulation and mediator release in allergic inflammation. We found that Tim-1 requires a tyrosine phosphorylation motif in its cytoplasmic tail to co-stimulate NF-AT/ AP1, NF-κB, and IL-6 promoter transcriptional activation as well as IL-6 cytokine secretion. Furthermore, IgE-Ag and Tim-1 costimulation of BMMCs using a panel of Tim-1 antibodies and its ligand Tim-4 demonstrate that IL-6 and TNF-alpha secretion can be modulated by activity of agonistic and blocking Tim-1 antibodies. These studies suggest that Tim-1 may serve as an important modulator of mast cell effector functions in atopic diseases.

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11

Xiao, Sheng, Craig R. Brooks, Chen Zhu, Chuan Wu, Johanna M. Sweere, Sonia Petecka, Ada Yeste, et al. "Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice." Proceedings of the National Academy of Sciences 109, no. 30 (July 5, 2012): 12105–10. http://dx.doi.org/10.1073/pnas.1120914109.

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12

Nakae, Susumu, Motoyasu Iikura, Hajime Suto, Hisaya Akiba, Dale T. Umetsu, Rosemarie H. DeKruyff, Hirohisa Saito, and Stephen J. Galli. "TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells." Blood 110, no. 7 (October 1, 2007): 2565–68. http://dx.doi.org/10.1182/blood-2006-11-058800.

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Members of the T-cell immunoglobulin– and mucin-domain–containing molecule (TIM) family have roles in T-cell–mediated immune responses. TIM-1 and TIM-2 are predominantly expressed on T helper type 2 (Th2) cells, whereas TIM-3 is preferentially expressed on Th1 and Th17 cells. We found that TIM-1 and TIM-3, but neither TIM-2 nor TIM-4, were constitutively expressed on mouse peritoneal mast cells and bone marrow–derived cultured mast cells (BMCMCs). After IgE + Ag stimulation, TIM-1 expression was down-regulated on BMCMCs, whereas TIM-3 expression was up-regulated. We also found that recombinant mouse TIM-4 (rmTIM-4), which is a ligand for TIM-1, as well as an anti–TIM-3 polyclonal Ab, can promote interleukin-4 (IL-4), IL-6, and IL-13 production without enhancing degranulation in BMCMCs stimulated with IgE + Ag. Moreover, the anti–TIM-3 Ab, but neither anti–TIM-1 Ab nor rmTIM-4, suppressed mast-cell apoptosis. These observations suggest that TIM-1 and TIM-3 may be able to influence T-cell–mediated immune responses in part through effects on mast cells.

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13

Vega-Carrascal, I., E. P. Reeves, S. J. O'Neill, and N. G. McElvaney. "Altered expression of T-cell immunoglobulin and mucin-domain-containing molecule-1 (TIM-1) and TIM-3 in the cystic fibrosis airway." Journal of Cystic Fibrosis 9 (June 2010): S46. http://dx.doi.org/10.1016/s1569-1993(10)60177-4.

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14

Hu, Sijun, Yong Xie, Nanjin Zhou, Lei Jin, Yan Tan, Dongsheng Liu, Yanfeng Gong, et al. "Expression of T-cell Immunoglobulin- and Mucin-domain-containing Molecules-1 and -3 (Tim-1 and Tim-3) in Helicobacter pylori Infection." Helicobacter 16, no. 5 (September 19, 2011): 373–81. http://dx.doi.org/10.1111/j.1523-5378.2011.00855.x.

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15

Dabbagh, Deemah, Sijia He, Brian Hetrick, Linda Chilin, Ali Andalibi, and Yuntao Wu. "Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors." Viruses 13, no. 5 (May 4, 2021): 832. http://dx.doi.org/10.3390/v13050832.

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Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.

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16

Kondratowicz, A. S., N. J. Lennemann, P. L. Sinn, R. A. Davey, C. L. Hunt, S. Moller-Tank, D. K. Meyerholz, et al. "T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus." Proceedings of the National Academy of Sciences 108, no. 20 (May 2, 2011): 8426–31. http://dx.doi.org/10.1073/pnas.1019030108.

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17

Lin, Jean Y., Meghan M. Delmastro, and Lawrence P. Kane. "Regulation of Tim-1 signaling and localization in T cell activation (35.35)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 35.35. http://dx.doi.org/10.4049/jimmunol.182.supp.35.35.

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Abstract T cell immunoglobulin and mucin domain 1 (Tim-1) can modulate CD4+ T helper responses. However, the precise mechanisms by which Tim-1 regulates T cell function remain relatively undefined. Work in this study focuses on identifying downstream targets of Tim-1 signaling as well as understanding Tim-1 localization during T cell activation. The consequences of Tim-1 interaction with antibodies or its ligand phosphatidylserine (PS) were explored by luciferase assays to determine levels of NFAT/AP-1 or by Western blotting for Tim-1 induced phosphorylation. Confocal microscopy was used to visualize Tim-1 localization on T cells after transfection of tagged forms of Tim-1 into D10 cells and incubation with antigen loaded antigen presenting cells (APCs). Results/Conclusions: Agonistic Tim-1 antibodies induce a previously unrecognized phosphorylated substrate, which we are currently attempting to identify. No induction of NFAT/AP-1 after interaction with PS expression apoptotic cells was apparent. Tim-1 localizes away from the immunological synapse after T cell activation. Better understanding of Tim-1 interactions with its antibodies, ligands, and APCs will allow for better understanding Tim-1 activation. NCI and NIAID

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18

Rhein, Bethany A., Rachel B. Brouillette, Grace A. Schaack, John A. Chiorini, and Wendy Maury. "Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry." Journal of Virology 90, no. 13 (April 27, 2016): 6097–111. http://dx.doi.org/10.1128/jvi.00100-16.

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ABSTRACTPhosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of theFiloviridaefamily of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion–TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions.IMPORTANCEWith more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor.

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19

Chu, Li-Wei, Chia-Jui Yang, Kuan-Jen Peng, Pei-Ling Chen, Shuu-Jiun Wang, and Yueh-Hsin Ping. "TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy." International Journal of Molecular Sciences 20, no. 19 (October 2, 2019): 4893. http://dx.doi.org/10.3390/ijms20194893.

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Dengue virus (DENV) infection triggers the activation of autophagy to facilitate the viral replication cycle from various aspects. Although a number of stimulators are proposed to activate autophagy, none of them appears prior to the uncoating process. Given that T-cell immunoglobulin and mucin domain 1 (TIM-1) receptor is a putative DENV receptor and promotes apoptotic body clearance by autophagy induction, it raises the possibility that TIM-1 may participate in the activation of DENV-induced autophagy. In this study, confocal images first revealed the co-localization of TIM-1 with autophagosomes in DENV-induced autophagy rather than rapamycin-induced autophagy, suggesting the co-transportation of TIM-1 with DENV during infection. The treatment of siRNA to knockdown TIM-1 expression in DENV-infected GFP-microtubule-associated protein light chain 3 (LC3)-Huh7.5 cells revealed that TIM-1 is required not only for DENV cellular internalization but also for autophagy activation. Furthermore, knockdown p85, a subunit of phosphoinositide 3-kinases (PI3Ks), which is co-localized with TIM-1 at rab5-positive endosomes caused the reduction of autophagy, indicating that TIM-1-mediated DENV-induced autophagy requires p85. Taken together, the current study uncovered TIM-1 as a novel factor for triggering autophagy in DENV infection through TIM-1-p85 axis, in addition to serving as a DENV receptor.

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20

Sampaio, S. O., X. Li, M. Takeuchi, C. Mei, U. Francke, E. C. Butcher, and M. J. Briskin. "Organization, regulatory sequences, and alternatively spliced transcripts of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) gene." Journal of Immunology 155, no. 5 (September 1, 1995): 2477–86. http://dx.doi.org/10.4049/jimmunol.155.5.2477.

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Abstract The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is expressed selectively at venular sites of lymphocyte extravasation into mucosal lymphoid tissues and lamina propria, where it directs local lymphocyte trafficking. MAdCAM-1 is a multifunctional type l transmembrane adhesion molecule comprising two distal lg domains involved in alpha 4 beta 7 integrin binding, a mucin-like region able to display L-selectin-binding carbohydrates, and a membrane-proximal lg domain homologous to lgA. We show in this work that the MAdCAM-1 gene is located on chromosome 10 and contains five exons. The signal peptide and each one of the three lg domains are encoded by a distinct exon, whereas the transmembrane, cytoplasmic tail, and 3'-untranslated region of MAdCAM-1 are combined on a single exon. The mucin-like region and the third lg domain are encoded together on exon 4. An alternatively spliced MAdCAM-1 mRNA is identified that lacks the mucin/lgA-homologous exon 4-encoded sequences. This short variant of MAdCAM-1 may be specialized to support alpha 4 beta 7-dependent adhesion strengthening, independent of carbohydrate-presenting function. Sequences 5' of the transcription start site include tandem nuclear factor-kappa B sites; AP-1, AP-2, and signal peptide-1 binding sites; and an estrogen response element. Our findings reinforce the correspondence between the multidomain structure and versatile functions of this vascular addressin, and suggest an additional level of regulation of carbohydrate-presenting capability, and thus of its importance in lectin-mediated vs alpha 4 beta 7-dependent adhesive events in lymphocyte trafficking.

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Biasin, Mara, Manuela Sironi, Irma Saulle, Chiara Pontremoli, Micaela Garziano, Rachele Cagliani, Daria Trabattoni, et al. "A 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 confers protections against HIV-1 infection." Microbes and Infection 19, no. 1 (January 2017): 69–74. http://dx.doi.org/10.1016/j.micinf.2016.09.005.

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Hayashi, Toshiaki, Tohru Takahashi, Satoshi Motoya, Tadao Ishida, Fumio Itoh, Masaaki Adachi, Yuji Hinoda, and Kohzoh Imai. "MUC1 Mucin Core Protein Binds to the Domain 1 of ICAM-1." Digestion 63, no. 1 (2001): 87–92. http://dx.doi.org/10.1159/000051917.

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23

Ballester, Beatriz, Javier Milara, and Julio Cortijo. "The role of mucin 1 in respiratory diseases." European Respiratory Review 30, no. 159 (February 2, 2021): 200149. http://dx.doi.org/10.1183/16000617.0149-2020.

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Recent evidence has demonstrated that mucin 1 (MUC1) is involved in many pathological processes that occur in the lung. MUC1 is a transmembrane protein mainly expressed by epithelial and hematopoietic cells. It has a receptor-like structure, which can sense the external environment and activate intracellular signal transduction pathways through its cytoplasmic domain. The extracellular domain of MUC1 can be released to the external environment, thus acting as a decoy barrier to mucosal pathogens, as well as serving as a serum biomarker for the diagnosis and prognosis of several respiratory diseases such as lung cancer and interstitial lung diseases. Furthermore, bioactivated MUC1-cytoplasmic tail (CT) has been shown to act as an anti-inflammatory molecule in several airway infections and mediates the expression of anti-inflammatory genes in lung diseases such as chronic rhinosinusitis, chronic obstructive pulmonary disease and severe asthma. Bioactivated MUC1-CT has also been reported to interact with several effectors linked to cellular transformation, contributing to the progression of respiratory diseases such as lung cancer and pulmonary fibrosis. In this review, we summarise the current knowledge of MUC1 as a promising biomarker and drug target for lung disease.

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Panchamoorthy, Govind, Hala Rehan, Akriti Kharbanda, Rehan Ahmad, and Donald Kufe. "A Monoclonal Antibody Against the Oncogenic Mucin 1 Cytoplasmic Domain." Hybridoma 30, no. 6 (December 2011): 531–35. http://dx.doi.org/10.1089/hyb.2011.0070.

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25

Funk, Christopher, Christopher Petersen, Neera Jagirdar, Sruthi Ravindranathan, David Jaye, Christopher Flowers, Amelia Langston, and Edmund Waller. "Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report." International Journal of Molecular Sciences 19, no. 12 (December 19, 2018): 4118. http://dx.doi.org/10.3390/ijms19124118.

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Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944). For two months post-infusion, the patient experienced dramatic regression of subcutaneous nodules of DLBCL. Unfortunately, her CAR T exhibited kinetics unassociated with remission, and she died of DLBCL-related sequelae. Serial phenotypic analysis of peripheral blood alongside sequencing of the β-peptide variable region of the T cell receptor (TCRβ) revealed distinct waves of oligoclonal T cell expansion with dynamic expression of immune checkpoint molecules. One week prior to CAR T cell contraction, T cell immunoglobulin mucin domain 3 (Tim-3) and programmed cell death protein 1 (PD-1) exhibited peak expressions on both the CD8 T cell (Tim-3 ≈ 50%; PD-1 ≈ 17%) and CAR T cell subsets (Tim-3 ≈ 78%; PD-1 ≈ 40%). These correlative observations draw attention to Tim-3 and PD-1 signaling pathways in context of CAR T cell exhaustion.

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Kansakar, Urna, Jessica Gambardella, Fahimeh Varzideh, Roberta Avvisato, Stanislovas S. Jankauskas, Pasquale Mone, Alessandro Matarese, and Gaetano Santulli. "miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections." International Journal of Molecular Sciences 23, no. 18 (September 6, 2022): 10242. http://dx.doi.org/10.3390/ijms231810242.

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T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.

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Shyjan, A. M., M. Bertagnolli, C. J. Kenney, and M. J. Briskin. "Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme divergence of mucin-like sequences." Journal of Immunology 156, no. 8 (April 15, 1996): 2851–57. http://dx.doi.org/10.4049/jimmunol.156.8.2851.

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Abstract The mucosal vascular addressin, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), is an Ig family adhesion receptor preferentially expressed by venular endothelial cells at sites of lymphocyte extravasation in murine mucosal lymphoid tissues and lamina propria. MAdCAM-1 specifically binds both human and mouse lymphocytes that express the homing receptor for Peyer's patches, the integrin alpha 4 beta 7. Functional expression cloning was used to isolate a cDNA from a macaque mesenteric lymph node library that encodes the homologue to murine MAdCAM-1. The macaque cDNA was subsequently used to clone the human homologue as well. Expression of human MAdCAM-1 RNA is restricted to mucosal tissues, gut-associated lymphoid tissues and spleen. Human MAdCAM-1 selectively binds both murine and human lymphocyte cell lines expressing alpha 4 beta 7. Human and macaque MAdCAM-1 have two Ig-like domains that are similar to the two amino-terminal integrin binding domains of murine MAdCAM-1. The conservation of sequences within the region homologous to the mucin/IgA domain of murine MAdCAM-1 is, however, much less apparent. These receptors exhibit considerable variation from murine MAdCAM-1 with respect to the length of the mucin-like sequence and the lack of a membrane proximal Ig (IgA-like) domain. The isolation of these different species of MAdCAM-1 demonstrates greater seleoffctive pressure for maintenance of amino acids involved in alpha 4 beta 7 binding than those sequences presumably involved in the presentation of carbohydrates for selectin binding.

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Zalewska, A., K. Zwierz, K. Zółkowski, and A. Gindzieński. "Structure and biosynthesis of human salivary mucins." Acta Biochimica Polonica 47, no. 4 (December 31, 2000): 1067–79. http://dx.doi.org/10.18388/abp.2000_3960.

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Human salivary glands secrete two types of mucins: oligomeric mucin (MG1) with molecular mass above 1 MDa and monomeric mucin (MG2) with molecular mass of 200-250 kDa. Monomers of MG1 and MG2 contain heavily O-glycosylated tandem repeats located at the central domain of the molecules. MG1 monomers are linked by disulfide bonds located at sparsely glycosylated N- and C-end. MG1 are synthesized by mucous cells and MG2 by the serous cells of human salivary glands.

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29

Xiao, Sheng, Nader Najafian, Jay Reddy, Monica Albin, Chen Zhu, Eric Jensen, Jaime Imitola, et al. "Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function." Journal of Experimental Medicine 204, no. 7 (July 2, 2007): 1691–702. http://dx.doi.org/10.1084/jem.20062498.

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It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti–Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-γ and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti–Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-γ and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti–Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged.

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Chakravarti, Sumone, Catherine A. Sabatos, Sheng Xiao, Zsolt Illes, Eugene K. Cha, Raymond A. Sobel, Xin X. Zheng, Terry B. Strom, and Vijay K. Kuchroo. "Tim-2 regulates T helper type 2 responses and autoimmunity." Journal of Experimental Medicine 202, no. 3 (July 25, 2005): 437–44. http://dx.doi.org/10.1084/jem.20050308.

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Identification of the T cell immunoglobulin mucin-domain containing (Tim) gene family introduced a new family of cell surface molecules that is involved in the regulation of immune responses. We previously demonstrated that Tim-3 is expressed on terminally differentiated T helper (Th)1 cells, and serves to regulate Th1 immune responses. Here, we describe the identification and function of Tim-2, a novel member of the Tim gene family. In contrast with Tim-3, we demonstrate that Tim-2 is expressed preferentially in differentiated Th2 cells. Blockade of the Tim-2/Tim-2 ligand interaction, by administration of soluble Tim-2 fusion protein (Tim-2 immunoglobulin [Ig]), results in T cell hyperproliferation and the production of Th2 cytokines. Administration of Tim-2 Ig during the induction phase reduces the severity of experimental autoimmune encephalomyelitis, a Th1-mediated autoimmune disease model of multiple sclerosis. We propose that Tim-2, an orthologue of human Tim-1, is critical for the regulation of Th2 responses during autoimmune inflammation.

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Elahi, Shokrollah, Toshiro Niki, Mitsuomi Hirashima, and Helen Horton. "Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection." Blood 119, no. 18 (May 3, 2012): 4192–204. http://dx.doi.org/10.1182/blood-2011-11-389585.

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Abstract Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4+ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4+ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4+ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection.

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Xiao, Sheng, and Vijay Kuchroo. "Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation (IRC11P.435)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 197.17. http://dx.doi.org/10.4049/jimmunol.194.supp.197.17.

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Abstract T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss of function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multi-organ tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3+ and IL-10-producing type 1 regulatory T (Tr1) cells) and enhance the severity of experimental autoimmune encephalomyelitis (EAE). Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with AC reduces EAE severity in wildtype (WT) but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.

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Golden-Mason, Lucy, Brent E. Palmer, Nasim Kassam, Lisa Townshend-Bulson, Stephen Livingston, Brian J. McMahon, Nicole Castelblanco, Vijay Kuchroo, David R. Gretch, and Hugo R. Rosen. "Negative Immune Regulator Tim-3 Is Overexpressed on T Cells in Hepatitis C Virus Infection and Its Blockade Rescues Dysfunctional CD4+ and CD8+ T Cells." Journal of Virology 83, no. 18 (July 8, 2009): 9122–30. http://dx.doi.org/10.1128/jvi.00639-09.

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ABSTRACT A number of emerging molecules and pathways have been implicated in mediating the T-cell exhaustion characteristic of chronic viral infection. Not all dysfunctional T cells express PD-1, nor are they all rescued by blockade of the PD-1/PD-1 ligand pathway. In this study, we characterize the expression of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) in chronic hepatitis C infection. For the first time, we found that Tim-3 expression is increased on CD4+ and CD8+ T cells in chronic hepatitis C virus (HCV) infection. The proportion of dually PD-1/Tim-3-expressing cells is greatest in liver-resident T cells, significantly more so in HCV-specific than in cytomegalovirus-specific cytotoxic T lymphocytes. Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127low CD57high), a central rather than effector memory profile (CD45RAnegative CCR7high), and reduced Th1/Tc1 cytokine production. We also demonstrate the ability to enhance T-cell proliferation and gamma interferon production in response to HCV-specific antigens by blocking the Tim-3-Tim-3 ligand interaction. These findings have implications for the development of novel immunotherapeutic approaches to this common viral infection.

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Shon, D. Judy, Stacy A. Malaker, Kayvon Pedram, Emily Yang, Venkatesh Krishnan, Oliver Dorigo, and Carolyn R. Bertozzi. "An enzymatic toolkit for selective proteolysis, detection, and visualization of mucin-domain glycoproteins." Proceedings of the National Academy of Sciences 117, no. 35 (August 17, 2020): 21299–307. http://dx.doi.org/10.1073/pnas.2012196117.

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Densely O-glycosylated mucin domains are found in a broad range of cell surface and secreted proteins, where they play key physiological roles. In addition, alterations in mucin expression and glycosylation are common in a variety of human diseases, such as cancer, cystic fibrosis, and inflammatory bowel diseases. These correlations have been challenging to uncover and establish because tools that specifically probe mucin domains are lacking. Here, we present a panel of bacterial proteases that cleave mucin domains via distinct peptide- and glycan-based motifs, generating a diverse enzymatic toolkit for mucin-selective proteolysis. By mutating catalytic residues of two such enzymes, we engineered mucin-selective binding agents with retained glycoform preferences. StcEE447Dis a pan-mucin stain derived from enterohemorrhagicEscherichia colithat is tolerant to a wide range of glycoforms. BT4244E575Aderived fromBacteroides thetaiotaomicronis selective for truncated, asialylated core 1 structures commonly associated with malignant and premalignant tissues. We demonstrated that these catalytically inactive point mutants enable robust detection and visualization of mucin-domain glycoproteins by flow cytometry, Western blot, and immunohistochemistry. Application of our enzymatic toolkit to ascites fluid and tissue slices from patients with ovarian cancer facilitated characterization of patients based on differences in mucin cleavage and expression patterns.

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35

Nishikori, Momoko, Wataru Kishimoto, Hiroshi Arima, Kotaro Shirakawa, Toshio Kitawaki, and Akifumi Takaori-Kondo. "Expression of Tim-1 and Its Pathogenetic Role in Primary CNS Lymphoma." Blood 124, no. 21 (December 6, 2014): 2961. http://dx.doi.org/10.1182/blood.v124.21.2961.2961.

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Abstract Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that arises within the central nervous system (CNS) as a primary lesion, most of which demonstrate diffuse large B-cell lymphoma (DLBCL) histology. However, CNS is recognized as an “immune sanctuary”, and it is not clear in what mechanism B cells develop tumor at this immunoprivileged site. In the past mouse models of multiple sclerosis and cerebral infarction, regulatory B cells, a population of B cells with high IL-10 producing capacity, were reported to have a function to migrate to CNS and suppress inflammation. As the IL-10 level is typically increased in the cerebrospinal fluid (CSF) of PCNSL patients, we hypothesized that PCNSL might originate from B cells that have a physiological role to produce IL-10 for suppressing unfavorable inflammation in CNS, such as regulatory B cells in mice. Recently, a cell surface molecule T cell immunoglobulin domain and mucin domain protein 1 (Tim-1) has been reported to be specifically expressed in the majority of regulatory B cells in mice. Tim-1 was originally identified as a costimulatory molecule on T cells that negatively regulates cellular immune response. Regulatory B cells in mice with defective Tim-1 mutation were reported to demonstrate a profound defect in IL-10 production, suggesting that Tim-1 plays an essential role in their IL-10 production. However, there has been no previous report on Tim-1 expression on human B-cells or B-cell lymphomas, or what function they may serve if it is present. We performed immunohistochemical staining of Tim-1 in various formalin-fixed paraffin embedded lymphoma samples. We observed strong expression of Tim-1 in PCNSL samples, in contrast to its lower expression in other DLBCL and follicular lymphoma samples. Expression of Tim-1 is also detected in a cell line derived from PCNSL (TK), as well as in several other B-cell lymphoma cell lines, by RT-PCR and western blot. As we detected spontaneous shedding of the ectodomain of Tim-1 in the culture media of Tim-1-expressing B-cell lymphoma cell lines, we examined whether Tim-1 can also be detected in the CSF of PCNSL patients. By ELISA, we detected soluble Tim-1 in the CSF of PCNSL patients with active disease, and found it undetectable after the successful treatment with chemo/radiotherapy. The level of soluble Tim-1 in the CSF was positively correlated with IL-10, and it is suggested that these two molecules are functionally related also in humans. In a patient with continuous Tim-1 detection in the CSF after chemotherapy while radiological examination could no longer detected any abnormality, subsequently manifested relapse in the brain. According to these findings, soluble Tim-1 in CSF may be expected to serve as a sensitive biomarker for PCNSL. To clarify the biological role of soluble Tim-1 in tumor microenvironment, we examined its effect on T cell function. We stimulated CD4+ and CD8+ T cells with or without soluble Tim-1 in vitro and compared their cytokine production. The result showed that, in the presence of soluble Tim-1, both IL-2 and IFN-g production was suppressed in CD8+ T cells. In conclusion, Tim-1 is expressed in PCNSL and shedding of extracellular domain of Tim-1, in addition to IL-10, may contribute to the immunosuppressive microenvironment of PCNSL. Disclosures No relevant conflicts of interest to declare.

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Noguera, Martín E., Jean Jakoncic, and Mario R. Ermácora. "High-resolution structure of intramolecularly proteolyzed human mucin-1 SEA domain." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1868, no. 3 (March 2020): 140361. http://dx.doi.org/10.1016/j.bbapap.2020.140361.

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Li, Minghua, Abdul A. Waheed, Jingyou Yu, Cong Zeng, Hui-Yu Chen, Yi-Min Zheng, Amin Feizpour, et al. "TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins." Proceedings of the National Academy of Sciences 116, no. 12 (March 6, 2019): 5705–14. http://dx.doi.org/10.1073/pnas.1819475116.

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The T cell Ig and mucin domain (TIM) proteins inhibit release of HIV-1 and other enveloped viruses by interacting with cell- and virion-associated phosphatidylserine (PS). Here, we show that the Nef proteins of HIV-1 and other lentiviruses antagonize TIM-mediated restriction. TIM-1 more potently inhibits the release of Nef-deficient relative to Nef-expressing HIV-1, and ectopic expression of Nef relieves restriction. HIV-1 Nef does not down-regulate the overall level of TIM-1 expression, but promotes its internalization from the plasma membrane and sequesters its expression in intracellular compartments. Notably, Nef mutants defective in modulating membrane protein endocytic trafficking are incapable of antagonizing TIM-mediated inhibition of HIV-1 release. Intriguingly, depletion of SERINC3 or SERINC5 proteins in human peripheral blood mononuclear cells (PBMCs) attenuates TIM-1 restriction of HIV-1 release, in particular that of Nef-deficient viruses. In contrast, coexpression of SERINC3 or SERINC5 increases the expression of TIM-1 on the plasma membrane and potentiates TIM-mediated inhibition of HIV-1 production. Pulse-chase metabolic labeling reveals that the half-life of TIM-1 is extended by SERINC5 from <2 to ∼6 hours, suggesting that SERINC5 stabilizes the expression of TIM-1. Consistent with a role for SERINC protein in potentiating TIM-1 restriction, we find that MLV glycoGag and EIAV S2 proteins, which, like Nef, antagonize SERINC-mediated diminishment of HIV-1 infectivity, also effectively counteract TIM-mediated inhibition of HIV-1 release. Collectively, our work reveals a role of Nef in antagonizing TIM-1 and highlights the complex interplay between Nef and HIV-1 restriction by TIMs and SERINCs.

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Hafler, David A., and Vijay Kuchroo. "TIMs: central regulators of immune responses." Journal of Experimental Medicine 205, no. 12 (November 17, 2008): 2699–701. http://dx.doi.org/10.1084/jem.20082429.

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Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.

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Gielen, Alexander W., Anna Lobell, Olle Lidman, Mohsen Khademi, Tomas Olsson, and Fredrik Piehl. "Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems." Journal of Neuroimmunology 164, no. 1-2 (July 2005): 93–104. http://dx.doi.org/10.1016/j.jneuroim.2005.04.004.

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40

Hattori, Takanari, Takeshi Saito, Hiroko Miyamoto, Masahiro Kajihara, Manabu Igarashi, and Ayato Takada. "Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells." Viruses 14, no. 10 (September 26, 2022): 2124. http://dx.doi.org/10.3390/v14102124.

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Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.

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Kikushige, Yoshikane, Junichiro Yuda, Takahiro Shima, Toshihiro Miyamoto, and Koichi Akashi. "TIM-3, a Leukemia Stem Cell Marker, Plays a Role In Leukemic Transformation Through Autocrine Stimulatory Signaling By Its Ligand, Galectin-9." Blood 122, no. 21 (November 15, 2013): 4196. http://dx.doi.org/10.1182/blood.v122.21.4196.4196.

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Abstract Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We have reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML but not on normal hematopoietic stem cells (HSCs) (Kikushige et al, Cell Stem Cell, 2010). We extended the analysis of TIM-3 expression into various types of human hematological malignancies, and found that human TIM-3 is expressed in the vast majority of CD34+CD38- LSCs of human myeloid malignancies including chronic myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes (MDS). Although CD34+CD38- normal bone marrow stem cells do not express TIM-3, TIM-3 is expressed in the CD34+CD38- population in MDS, and is further up-regulated with progression into leukemia. The average percentages of TIM-3+ cells in the CD34+CD38- population was 7.8% in RCMD (n=10), 19.2% in RAEB-1 (n=10), 84.0% in RAEB-2 (n=10) and 92.2% in overt AML (n=10). The close association of TIM-3 expression with transformation into AML led us to hypothesize that TIM-3 itself has a function in AML stem cell development. TIM-3 is a type 1 cell-surface glycoprotein and has a structure that includes an N-terminal immunoglobulin variable domain followed by a mucin domain, a transmembrane domain and a cytoplasmic tail. Tyrosine residues are clustered in the cytoplasmic tail, suggesting that TIM-3 can induce signal transduction in TIM-3+ AML cells. To understand the function of TIM-3, we investigated the interaction between TIM-3 and its ligand galectin-9 in AML LSCs. We found that AML patients showed significantly higher serum galectin-9 concentration than healthy individuals (healthy controls: 18.3+4.3 pg/ml, AML patients: 139.1+33.4 pg/ml, P<0.05). Unexpectedly, we found that leukemic cells expressed a high level of galectin-9 protein, as compared to other hematopoietic cells including T cells, B cells and monocytes. Using KASUMI-3 (TIM-3+ AML cell line) and primary AML samples, we confirmed that AML cells could secrete galectin-9 after TLR stimulation in vitro. Furthermore, microarray analysis demonstrated that TIM-3 stimulation by the physiological concentration of galectin-9 induced significant gene expression changes toward pro-survival axis including up-regulation of MCL-1, the important survival factor for HSCs and LSCs. These results collectively suggest that AML cells can produce and secrete galectin-9, and galectin-9 can bind and stimulate TIM-3-expressing AML cells including LSCs in an autocrine manner to support their survival or leukemia progression. Disclosures: Miyamoto: Kyushu University Hospital: Employment.

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Kuroda, Makoto, Daisuke Fujikura, Asuka Nanbo, Andrea Marzi, Osamu Noyori, Masahiro Kajihara, Junki Maruyama, et al. "Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus." Journal of Virology 89, no. 12 (April 8, 2015): 6481–93. http://dx.doi.org/10.1128/jvi.03156-14.

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ABSTRACTMultiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections.IMPORTANCEFiloviruses, including Ebola and Marburg viruses, cause rapidly fatal diseases in humans and nonhuman primates. There are currently no approved vaccines or therapeutics for filovirus diseases. In general, the cellular entry step of viruses is one of the key mechanisms to develop antiviral strategies. However, the molecular mechanisms underlying the entry process of filoviruses have not been fully understood. In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for filovirus entry, interact in the intracellular vesicles where Ebola virus GP-mediated membrane fusion occurs and that this interaction is important for filovirus infection. We found that filovirus infection and GP-mediated membrane fusion in cultured cells were remarkably suppressed by treatment with a TIM-1-specific monoclonal antibody that interfered with the interaction between TIM-1 and NPC1. Our data provide new insights for the development of antiviral compounds that can be universally used against filovirus infections.

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Manandhar, Priyanka, Emily Elizabeth Landy, Benjamin Murter, Hridesh Banerjee, Andrea Workman, Isabella Bosco, and Lawrence P. Kane. "Mechanism of Tim-3 regulation of CD8+ T cell function." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 55.04. http://dx.doi.org/10.4049/jimmunol.208.supp.55.04.

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Abstract Tim-3 or transmembrane immunoglobulin and mucin domain-3 is a type I membrane protein expressed by various immune cell types, and has been shown to have a co-stimulatory role in T cells through the PI3K pathway. Tim-3 comprises extracellular, transmembrane and intracellular domains, the latter of which contains five tyrosine residues. We and others have shown that these tyrosines participate in TCR-mediated signaling pathways. Using LCMV infection, we also found that Tim-3 expression influences the formation of short-lived effector and memory precursor CD8+ T cells. We hypothesize that Tim-3 signaling through the tyrosine residues in its cytoplasmic domain modulates CD8+ T cell activation and differentiation. To test this hypothesis, we have used LCMV-specific TCR transgenic (P14) mice crossed to truncated version of Tim-3 and CD8+ conditional deletion of Tim-3. CD8+ T cell activation and memory were analyzed by flow cytometry after infection with LCMV Armstrong to induce an acute infection. The effects of Tim-3 on CD8+ T cells were found to be most prominent at the effector stage of infection and RNA sequencing has shown that loss of Tim-3 signaling promotes acquisition of a memory-like phenotype. Transcription factors T-bet and Blimp-1 were found to be lower in Tim-3 KO CD8+ T cells, while Tcf-1 maintained at higher levels in the absence of Tim-3 signaling. Cytokine production by effector CD8+ T cells was also found to be lower when Tim-3 was absent. Thus, we conclude that Tim-3 signaling via its cytoplasmic tyrosine residues plays a role in CD8+ T cells in an acute infection. These results may lead to a better understanding of CD8+ T cell activation and memory development in different settings. Supported by R01 AI138504-01A1

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Kikushige, Yoshikane, Takahiro Shima, Junichiro Yuda, Toshihiro Miyamoto, and Koichi Akashi. "Leukemogenic Function of TIM-3, a Leukemia Stem Cell Marker, in Acute Myelogenous Leukemia and Myelodysplastic Syndromes." Blood 120, no. 21 (November 16, 2012): 2983. http://dx.doi.org/10.1182/blood.v120.21.2983.2983.

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Abstract Abstract 2983 Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We have reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML but not on normal hematopoietic stem cells (HSCs). TIM-3+ AML cells reconstituted human AML in immunodeficient mice, whereas TIM3− AML cells did not, suggesting that the TIM-3+ population contains all functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden, and eliminated LSCs capable of reconstituting human AML in secondary recipients (Kikushige et al, Cell Stem Cell, 2010).We extended the analysis of TIM-3 expression into various types of human hematological malignancies, and found that human TIM-3 is expressed in the vast majority of CD34+CD38− LSCs of human myeloid malignancies including chronic myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes (MDS). Although TIM-3 was not expressed in CD34+CD38− stem cell fraction in normal bone marrow cells, TIM-3 was progressively up-regulated in this population of MDS, along with disease progression into leukemia: The average percentages of TIM-3+ cells in the CD34+CD38− population was 7.8% in RCMD (n=10), 19.2% in RAEB-1 (n=10), 84.0% in RAEB-2 (n=10) and 92.2% in overt AML (n=10). Thus, TIM-3 might be useful to isolate malignant stem cells responsible for progression into AML in MDS patients. The close association of TIM-3 expression with transformation into AML led us to hypothesize that TIM-3 itself has a function in AML stem cell development. TIM-3 is type 1 cell-surface glycoprotein and has a structure that includes an N-terminal immunoglobulin variable domain followed by a mucin domain, a transmembrane domain and a cytoplasmic tail. Tyrosine residues are clustered in the cytoplasmic tail, suggesting that TIM-3 can induce signal transduction in TIM-3+ AML cells. Previous reports have shown that galectin-9 and HMGB-1 are the ligand of TIM-3 in lymphocytes and dendritic cells. TIM-3 is reported to signal differently in lymphocytes and myeloid cells, because TIM-3 ligation results in different patterns of tyrosine phosphorylation in these cell types, suggesting that TIM-3 has lineage- or cellular context-dependent signal transduction pathways or functions. Therefore, we considered that it should be critical to identify the function of TIM-3 in primary AML cells. We cultured TIM-3+ AML cells in the presence or absence of galectin-9 or HMGB-1, and performed cDNA microarray analysis to find genes activated in response to TIM-3 ligation. Interestingly, pro-apoptotic genes such as BAX and SIVA were significantly down-regulated in the presence of galectin-9 or HMGB-1, suggesting that TIM-3 signaling could promote survival of TIM-3-expressing LSCs. These data suggest that TIM-3 is a surface marker useful to track malignant LSCs in progression from MDS to AML, and TIM-3 may function for maintenance of LSC through inducing survival-promoting signaling. Disclosures: No relevant conflicts of interest to declare.

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Martín-Quirós, Alejandro, Charbel Maroun-Eid, José Avendaño-Ortiz, Roberto Lozano-Rodríguez, Jaime Valentín Quiroga, Verónica Terrón, Karla Montalbán-Hernández, et al. "Potential Role of the Galectin-9/TIM-3 Axis in the Disparate Progression of SARS-CoV-2 in a Married Couple: A Case Report." Biomedicine Hub 6, no. 1 (April 19, 2021): 48–58. http://dx.doi.org/10.1159/000514727.

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We report the disparate clinical progression of a couple infected by SARS-CoV-2 based on their immune checkpoint (IC) levels and immune cell distribution in blood from admission to exitus in patient 1 and from admission to discharge and recovery in patient 2. A detailed clinical follow-up accompanied by a longitudinal analysis of immune phenotypes and IC levels is shown. The continuous increase in the soluble IC ligand galectin-9 (Gal-9) and the increment in T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) protein in T cells in patient 1 suggests an activation of the Gal-9/TIM-3 axis and, subsequently, a potential cell exhaustion in this patient that did not occur in patient 2. Our data indicate that the Gal-9/TIM-3 axis could be a potential target in this clinical setting, along with a patent effector memory T-cell reduction.

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Mittelberger, Johanna, Marina Seefried, Manuela Franitza, Fabian Garrido, Nina Ditsch, Udo Jeschke, and Christian Dannecker. "The Role of the Immune Checkpoint Molecules PD-1/PD-L1 and TIM-3/Gal-9 in the Pathogenesis of Preeclampsia—A Narrative Review." Medicina 58, no. 2 (January 20, 2022): 157. http://dx.doi.org/10.3390/medicina58020157.

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Preeclampsia is a pregnancy-specific disease which is characterized by abnormal placentation, endothelial dysfunction, and systemic inflammation. Several studies have shown that the maternal immune system, which is crucial for maintaining the pregnancy by ensuring maternal-fetal-tolerance, is disrupted in preeclamptic patients. Besides different immune cells, immune checkpoint molecules such as the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1 system) and the T-cell immunoglobulin and mucin domain-containing protein 3/Galectin-9 (TIM-3/Gal-9 system) are key players in upholding the balance between pro-inflammatory and anti-inflammatory signals. Therefore, a clear understanding about the role of these immune checkpoint molecules in preeclampsia is essential. This review discusses the role of these two immune checkpoint systems in pregnancy and their alterations in preeclampsia.

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47

Sanchez, Angela J., Martin J. Vincent, Bobbie R. Erickson, and Stuart T. Nichol. "Crimean-Congo Hemorrhagic Fever Virus Glycoprotein Precursor Is Cleaved by Furin-Like and SKI-1 Proteases To Generate a Novel 38-Kilodalton Glycoprotein." Journal of Virology 80, no. 1 (January 1, 2006): 514–25. http://dx.doi.org/10.1128/jvi.80.1.514-525.2006.

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ABSTRACT Crimean-Congo hemorrhagic fever virus (genus Nairovirus, family Bunyaviridae) genome M segment encodes an unusually large (in comparison to members of other genera) polyprotein (1,684 amino acids in length) containing the two major structural glycoproteins, Gn and Gc, that are posttranslationally processed from precursors PreGn and PreGc by SKI-1 and SKI-1-like proteases, respectively. The characteristics of the N-terminal 519 amino acids located upstream of the mature Gn are unknown. A highly conserved furin/proprotein convertase (PC) cleavage site motif (RSKR247) is located between the variable N-terminal region that is predicted to have mucin-like properties and the rest of PreGn. Mutational analysis of the RSKR247 motif and use of a specific furin/PC inhibitor and brefeldin A demonstrate that furin/PC cleavage occurs at the RSKR247 motif of PreGn as the protein transits the trans Golgi network and generates a novel glycoprotein designated GP38. Immunoprecipitation analysis identified two additional proteins, GP85 and GP160, which contain both mucin and GP38 domain regions, and whose generation does not involve furin/PC cleavage. Consistent with glycosylation predictions, heavy O-linked glycosylation and moderate levels of N-glycans were detected in the GP85 and GP160 proteins, both of which contain the mucin domain. GP38, GP85, and GP160 are likely soluble proteins based on the lack of predicted transmembrane domains, their detection in virus-infected cell supernatants, and the apparent absence from virions. Analogy with soluble glycoproteins and mucin-like proteins encoded by other hemorrhagic fever-associated RNA viruses suggests these proteins could play an important role in viral pathogenesis.

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Xu, Geng, Lei Cheng, Ling Lu, Yi Zhu, Rui Xu, Xin Yao, and Huabin Li. "Expression of T-cell immunoglobulin- and mucin-domain-containing molecule-1 (TIM-1) is increased in a mouse model of asthma and relationship to GATA-3." Life Sciences 82, no. 11-12 (March 2008): 663–69. http://dx.doi.org/10.1016/j.lfs.2007.12.017.

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Ding, Qing, Melissa Yeung, Sheng Xiao, Nader Najafian, Vijay Kuchroo та David Rothstein. "Anti-TIM-4 mediates long-term engraftment of islet allografts by promoting IL-10 expression by TIM-1+ Bregs and inhibiting IFNγ expression by proinflammatory “Be1” B cells (IRC3P.464)". Journal of Immunology 192, № 1_Supplement (1 травня 2014): 59.7. http://dx.doi.org/10.4049/jimmunol.192.supp.59.7.

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Abstract We previously defined TIM-1 as an inclusive marker for IL-10+ regulatory B cells (Bregs). Moreover, α-TIM-1 mAb prolongs islet allograft survival (GS) through induction of TIM-1+ Bregs. We recently noted that TIM-4, a TIM-1 ligand, identifies B cells enriched for IFNγ (Be1). We therefore hypothesized that TIM-4 blockade should also prolong GS and that this may involve B cells. In fact, α-TIM-4 (RMT4-53) treatment resulted in long-term GS in BALB/c recipients of B6 islets (MST >100d). Moreover, α-TIM-4 increases Th2 cytokines (IL-4, IL-10) and Foxp3+Tregs, while reducing both Th1 cytokines (IFNγ) and CD4 proliferation. However, these α-TIM-4-mediated changes and long-term GS were B cell dependent, and did not occur in either B cell deficient (JHD) or depleted (α-CD20) recipients. To address whether α-TIM-4 directly targets (TIM-4+) Be1 cells, we showed that adoptive transfer of WT, but not TIM-4-/- B cells, into μMT recipients, reconstitutes long-term GS mediated by α-TIM-4. We also found that α-TIM-4 inhibits IFNγ expression by TIM-4+ B cells by 40%. Bregs were also required for α-TIM-4 induced transplant tolerance. Transfer of B cells from TIM-1Δmucin (mucin domain deletion) mice, which exhibit a defect in Bregs, is unable to prolong GS in B deficient mice. In wt mice, α-TIM-4 increases TIM-1+ IL-10+ Bregs by ~100%. Taken together, our data reveal that targeting TIM-4 enhances IL-10 expressing Bregs and also reduces inflammatory Be1 B cells to promote allograft tolerance.

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Saleh, Reem, Salman M. Toor, Dana Al-Ali, Varun Sasidharan Nair, and Eyad Elkord. "Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants." Genes 11, no. 6 (June 25, 2020): 703. http://dx.doi.org/10.3390/genes11060703.

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Immune checkpoint inhibitors (ICIs) are yet to have a major advantage over conventional therapies, as only a fraction of patients benefit from the currently approved ICIs and their response rates remain low. We investigated the effects of different ICIs—anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand-1 (PD-L1), and anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3)—on human primary breast cancer explant cultures using RNA-Seq. Transcriptomic data revealed that PD-1, PD-L1, and TIM-3 blockade follow unique mechanisms by upregulating or downregulating distinct pathways, but they collectively enhance immune responses and suppress cancer-related pathways to exert anti-tumorigenic effects. We also found that these ICIs upregulated the expression of other IC genes, suggesting that blocking one IC can upregulate alternative ICs, potentially giving rise to compensatory mechanisms by which tumor cells evade anti-tumor immunity. Overall, the transcriptomic data revealed some unique mechanisms of the action of monoclonal antibodies (mAbs) targeting PD-1, PD-L1, and TIM-3 in human breast cancer explants. However, further investigations and functional studies are warranted to validate these findings.

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