{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:17:54Z","timestamp":1791980274716,"version":"4.4.0"},"reference-count":68,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,12,14]]},"abstract":"<jats:p>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 (Fc\u03b5RI), 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 Fc\u03b5RI ligation.<\/jats:p>","DOI":"10.1084\/jem.20150388","type":"journal-article","created":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T02:33:15Z","timestamp":1448332395000},"page":"2289-2304","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":111,"title":["Tim-3 enhances Fc\u03b5RI-proximal signaling to modulate mast cell activation"],"prefix":"10.1084","volume":"212","author":[{"given":"Binh L.","family":"Phong","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 1"},{"name":"Graduate Program in Immunology, University of Pittsburgh, Pittsburgh, PA 15261 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsay","family":"Avery","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 1"},{"name":"Infectious Disease and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, PA 15261 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina L.","family":"Sumpter","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15261 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob V.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon C.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Colgan","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 6"},{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence P.","family":"Kane","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2015,11,23]]},"reference":[{"key":"2023072602405306100_bib1","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/nri2782","article-title":"Mast cell-orchestrated immunity to pathogens","volume":"10","author":"Abraham","year":"2010","journal-title":"Nat. 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