title: Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.
abstract: T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 Graduate Program in Immunology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Binh L
authors.initials: BL
authors.lastname: Phong
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 Infectious Disease and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Avery
authors.affiliation: Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Tina L
authors.initials: TL
authors.lastname: Sumpter
authors.affiliation: Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Gorman
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: John D
authors.initials: JD
authors.lastname: Colgan
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 lkane@pitt.edu.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D000072597:Hepatitis A Virus Cellular Receptor 2; D007073:Immunoglobulin E / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism*; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D000941:Antigens; C484266:Bag6 protein, mouse; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D003432:Cross-Linking Reagents; D016207:Cytokines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C539818:Nr4a1 protein, mouse; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D021122:Protein Subunits; D017455:Receptors, IgE; D011991:Receptors, Virus; D038601:Ribosomal Protein S6; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma