Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

• Published in: The Journal of experimental medicine Vol. 212; no. 13; pp. 2289 - 2304
• Main Authors: Phong, Binh L, Avery, Lyndsay, Sumpter, Tina L, Gorman, Jacob V, Watkins, Simon C, Colgan, John D, Kane, Lawrence P
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 14.12.2015
• Subjects: Animals; Antibodies - pharmacology; Antigens - immunology; Bone Marrow Cells - cytology; Carcinoembryonic Antigen - metabolism; Cell Degranulation - drug effects; Cross-Linking Reagents - pharmacology; Cytokines - biosynthesis; Hepatitis A Virus Cellular Receptor 2; Immunoglobulin E - immunology; Interleukin-6 - biosynthesis; Intracellular Signaling Peptides and Proteins - metabolism; Mast Cells - drug effects; Mast Cells - metabolism; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones - metabolism; Nuclear Proteins - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Phospholipase C gamma - metabolism; Phosphorylation - drug effects; Phosphotyrosine - metabolism; Protein Subunits - metabolism; Protein-Tyrosine Kinases - metabolism; Receptors, IgE - metabolism; Receptors, Virus - chemistry; Receptors, Virus - metabolism; Ribosomal Protein S6 - metabolism; Signal Transduction - drug effects; src-Family Kinases - metabolism; Syk Kinase; Transcriptional Activation - drug effects; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20150388

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.