{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T16:37:08Z","timestamp":1792859828380,"version":"4.5.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"905","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:p>TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.<\/jats:p>","DOI":"10.1126\/scisignal.adk4594","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T17:58:23Z","timestamp":1758650303000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["TIM3 is a context-dependent coregulator of cytotoxic T cell function"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3688-8454","authenticated-orcid":true,"given":"Hanin","family":"Alamir","sequence":"first","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6487-1125","authenticated-orcid":true,"given":"Carissa C. W.","family":"Wong","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."},{"name":"School of Medicine, University of Cardiff, Cardiff CF14 4XN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Alsubaiti","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9188-7345","authenticated-orcid":true,"given":"Grace L.","family":"Edmunds","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Alismail","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Huynh","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-2459","authenticated-orcid":true,"given":"Philip A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Proteomics Facility, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tressan","family":"Grant","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."},{"name":"Department of Life Sciences, University of Bath, Bath BA2 7AY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safaa","family":"Alsulaimani","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9048-1134","authenticated-orcid":true,"given":"James","family":"Boyd","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Holland","sequence":"additional","affiliation":[{"name":"ImmunoCore Ltd., Abingdon OX14 4RY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-0437","authenticated-orcid":true,"given":"David J.","family":"Morgan","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6675-7004","authenticated-orcid":true,"given":"Awen M.","family":"Gallimore","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Cardiff, Cardiff CF14 4XN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6156-9861","authenticated-orcid":true,"given":"Christoph","family":"W\u00fclfing","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.002"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0522-3"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712107115"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.579351"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000911"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni987"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.4161\/onci.23849"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.11.019"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02972-8"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aau4518"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0224-6"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.019"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00229"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI152864"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13848"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1385690"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201948400"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21099-2"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302663"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003253"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.05297-11"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aba0717"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00575-7"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5008"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000199"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e11-08-0731"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102609"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiq153"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13071-019-3788-x"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.9.5042"},{"key":"e_1_3_2_34_2","first-page":"e1328336","article-title":"CEACAM1 as a multi-purpose target for cancer immunotherapy","volume":"6","author":"Dankner M.","year":"2017","unstructured":"M. Dankner, S. D. Gray-Owen, Y.-H. Huang, R. S. Blumberg, N. Beauchemin, CEACAM1 as a multi-purpose target for cancer immunotherapy. Oncoimmunology 6, e1328336 (2017).","journal-title":"Oncoimmunology"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63433-5"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-01871-2"},{"key":"e_1_3_2_37_2","first-page":"177","article-title":"Galectin-9 in tumor biology: A jack of multiple trades","volume":"1836","author":"Heusschen R.","year":"2013","unstructured":"R. Heusschen, A. W. Griffioen, V. L. Thijssen, Galectin-9 in tumor biology: A jack of multiple trades. Biochim. Biophys. Acta 1836, 177\u2013185 (2013).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.016"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939274"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2871"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aay1863"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.014"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.731175"},{"issue":"1","key":"e_1_3_2_44_2","first-page":"E102","article-title":"Therapeutic potential of Galectin-9 in human disease","volume":"33","author":"Wiersma V. R.","year":"2013","unstructured":"V. R. Wiersma, M. de Bruyn, W. Helfrich, E. Bremer, Therapeutic potential of Galectin-9 in human disease. Med. Res. Rev. 33 (Suppl. 1) E102\u2013E126 (2013).","journal-title":"Med. Res. Rev."},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1775464"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101296"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210425"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140694"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00660.x"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-020-00377-6"},{"key":"e_1_3_2_51_2","first-page":"5302","article-title":"Mechanism and function of Vav1 localisation in TCR signalling","volume":"125","author":"Ksionda O.","year":"2012","unstructured":"O. Ksionda, A. Saveliev, R. K\u00f6chl, J. Rapley, M. Faroudi, J. E. Smith-Garvin, C. W\u00fclfing, K. Rittinger, T. Carter, V. L. Tybulewicz, Mechanism and function of Vav1 localisation in TCR signalling. J. Cell Sci. 125, 5302\u20135314 (2012).","journal-title":"J. Cell Sci."},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2001821"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.10.6407"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58653"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay5663"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12123"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1037"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.2.265"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706812"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1934-z"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw413"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1109\/TIT.1983.1056714"},{"key":"e_1_3_2_64_2","doi-asserted-by":"crossref","unstructured":"C. Ahlmann-Eltze S. Anders proDA: Probabilistic dropout analysis for identifying differentially abundant proteins in label-free mass spectrometry. bioRxiv 661496 [Preprint] (2020). https:\/\/doi.org\/10.1101\/661496.","DOI":"10.21203\/rs.3.rs-36351\/v1"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47899-w"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adk4594","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T17:58:25Z","timestamp":1758650305000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adk4594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":65,"journal-issue":{"issue":"905","published-print":{"date-parts":[[2025,9,23]]}},"alternative-id":["10.1126\/scisignal.adk4594"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adk4594","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]},"assertion":[{"value":"2023-08-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-27","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadk4594"}}