{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:57:52Z","timestamp":1791183472846,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>CD8+ CTLs are adept at killing virally infected cells and cancer cells and releasing cytokines (e.g., IFN-\u03b3) to aid this response. However, during cancer and chronic viral infections, such as with HIV, this CTL response is progressively impaired due to a process called T cell exhaustion. Previous work has shown that the glycoprotein T cell Ig and mucin domain\u2013containing protein 3 (Tim-3) plays a functional role in establishing T cell exhaustion. Tim-3 is highly upregulated on virus and tumor Ag-specific CD8+ T cells, and antagonizing Tim-3 helps restore function of CD8+ T cells. However, very little is known of how Tim-3 signals in CTLs. In this study, we assessed the role of Tim-3 at the immunological synapse as well as its interaction with proximal TCR signaling molecules in primary human CD8+ T cells. Tim-3 was found within CD8+ T cell lipid rafts at the immunological synapse. Blocking Tim-3 resulted in a significantly greater number of stable synapses being formed between Tim-3hiCD8+ T cells and target cells, suggesting that Tim-3 plays a functional role in synapse formation. Further, we confirmed that Tim-3 interacts with Lck, but not the phospho-active form of Lck. Finally, Tim-3 colocalizes with receptor phosphatases CD45 and CD148, an interaction that is enhanced in the presence of the Tim-3 ligand, galectin-9. Thus, Tim-3 interacts with multiple signaling molecules at the immunological synapse, and characterizing these interactions could aid in the development of therapeutics to restore Tim-3\u2013mediated immune dysfunction.<\/jats:p>","DOI":"10.4049\/jimmunol.1302663","type":"journal-article","created":{"date-parts":[[2013,12,13]],"date-time":"2013-12-13T22:19:59Z","timestamp":1386973199000},"page":"782-791","source":"Crossref","is-referenced-by-count":129,"title":["T Cell Ig and Mucin Domain\u2013Containing Protein 3 Is Recruited to the Immune Synapse, Disrupts Stable Synapse Formation, and Associates with Receptor Phosphatases"],"prefix":"10.1093","volume":"192","author":[{"given":"Kiera L","family":"Clayton","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S","family":"Haaland","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B","family":"Douglas-Vail","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shariq","family":"Mujib","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen M","family":"Chew","sequence":"additional","affiliation":[{"name":"Hawaii Center for AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawai\u2018i , Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishomwa C","family":"Ndhlovu","sequence":"additional","affiliation":[{"name":"Hawaii Center for AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawai\u2018i , Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario A","family":"Ostrowski","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]},{"name":"Clinical Sciences Division, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]},{"name":"Maple Leaf Clinic , Toronto, Ontario M5B 1L6,","place":["Canada"]},{"name":"Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital , Toronto, Ontario M5B 1W8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,15]]},"reference":[{"key":"2025032404084603200_r1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. 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Immunol."},{"key":"2025032404084603200_r26","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1128\/MCB.05297-11","article-title":"Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways","volume":"31","author":"Lee","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"2025032404084603200_r27","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/nm.2871","article-title":"Bat3 promotes T cell responses and autoimmunity by repressing Tim-3\u2013mediated cell death and exhaustion","volume":"18","author":"Rangachari","year":"2012","journal-title":"Nat. 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