{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:54:03Z","timestamp":1790805243040,"version":"4.1.0"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"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":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>T cell Ig and mucin domain (Tim) 3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes infection. Analysis of wild-type (WT) mice infected with L. monocytogenes revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to L. monocytogenes by WT and Tim-3 knockout (KO) mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-\u03b3 production and degranulation by Tim-3 KO cells stimulated with peptide Ag ex vivo. To address the T cell\u2013intrinsic role of Tim-3, we analyzed responses to L. monocytogenes infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection.<\/jats:p>","DOI":"10.4049\/jimmunol.1302290","type":"journal-article","created":{"date-parts":[[2014,2,25]],"date-time":"2014-02-25T01:13:11Z","timestamp":1393290791000},"page":"3133-3142","source":"Crossref","is-referenced-by-count":90,"title":["Tim-3 Directly Enhances CD8 T Cell Responses to Acute\n                    <i>Listeria monocytogenes<\/i>\n                    Infection"],"prefix":"10.1093","volume":"192","author":[{"given":"Jacob V","family":"Gorman","sequence":"first","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Starbeck-Miller","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhat-Long L","family":"Pham","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geri L","family":"Traver","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B","family":"Rothman","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Department of Microbiology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T","family":"Harty","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Department of Microbiology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Department of Pathology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D","family":"Colgan","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Department of Internal Medicine, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"},{"name":"Anatomy and Cell Biology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,4,1]]},"reference":[{"key":"2025032404213723500_r1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nri3405","article-title":"Molecular mechanisms of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025032404213723500_r2","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.4049\/jimmunol.0902937","article-title":"T cell Ig and mucin domain proteins and immunity","volume":"184","author":"Kane","year":"2010","journal-title":"J. Immunol."},{"key":"2025032404213723500_r3","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.0105-2896.2010.00903.x","article-title":"TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity","volume":"235","author":"Freeman","year":"2010","journal-title":"Immunol. Rev."},{"key":"2025032404213723500_r4","first-page":"1","article-title":"TIM-3 and its regulatory role in immune responses","volume":"350","author":"Zhu","year":"2011","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"2025032404213723500_r5","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nature06307","article-title":"Identification of Tim4 as a phosphatidylserine receptor","volume":"450","author":"Miyanishi","year":"2007","journal-title":"Nature"},{"key":"2025032404213723500_r6","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.immuni.2007.11.011","article-title":"TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells","volume":"27","author":"Kobayashi","year":"2007","journal-title":"Immunity"},{"key":"2025032404213723500_r7","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1182\/blood-2008-10-185884","article-title":"Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation","volume":"113","author":"Nakayama","year":"2009","journal-title":"Blood"},{"key":"2025032404213723500_r8","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.4049\/jimmunol.0903059","article-title":"T cell\/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells","volume":"184","author":"DeKruyff","year":"2010","journal-title":"J. Immunol."},{"key":"2025032404213723500_r9","doi-asserted-by":"crossref","first-page":"17113","DOI":"10.1073\/pnas.0508643102","article-title":"T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation","volume":"102","author":"de Souza","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404213723500_r10","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.4049\/jimmunol.180.10.6518","article-title":"T cell Ig and mucin domain-1-mediated T cell activation requires recruitment and activation of phosphoinositide 3-kinase","volume":"180","author":"de Souza","year":"2008","journal-title":"J. Immunol."},{"key":"2025032404213723500_r11","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.bbrc.2006.10.079","article-title":"A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9","volume":"351","author":"van de Weyer","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032404213723500_r12","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":"2025032404213723500_r13","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.molimm.2011.03.023","article-title":"Fyn binds to and phosphorylates T cell immunoglobulin and mucin domain-1 (Tim-1)","volume":"48","author":"Curtiss","year":"2011","journal-title":"Mol. 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Immunol."},{"key":"2025032404213723500_r18","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/415536a","article-title":"Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease","volume":"415","author":"Monney","year":"2002","journal-title":"Nature"},{"key":"2025032404213723500_r19","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/ni987","article-title":"Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance","volume":"4","author":"S\u00e1nchez-Fueyo","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032404213723500_r20","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.jhep.2009.12.005","article-title":"T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B","volume":"52","author":"Ju","year":"2010","journal-title":"J. Hepatol."},{"key":"2025032404213723500_r21","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1182\/blood-2011-06-360321","article-title":"Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9","volume":"119","author":"Gleason","year":"2012","journal-title":"Blood"},{"key":"2025032404213723500_r22","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1182\/blood-2011-11-392951","article-title":"Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity","volume":"119","author":"Ndhlovu","year":"2012","journal-title":"Blood"},{"key":"2025032404213723500_r23","doi-asserted-by":"crossref","first-page":"e1000882","DOI":"10.1371\/journal.ppat.1000882","article-title":"Galectin-9\/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response","volume":"6","author":"Sehrawat","year":"2010","journal-title":"PLoS Pathog."},{"key":"2025032404213723500_r24","doi-asserted-by":"crossref","first-page":"7660","DOI":"10.4049\/jimmunol.181.11.7660","article-title":"Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions","volume":"181","author":"Nagahara","year":"2008","journal-title":"J. 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Immunol."},{"key":"2025032404213723500_r33","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/ni988","article-title":"Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance","volume":"4","author":"Sabatos","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025032404213723500_r34","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.4049\/jimmunol.1300083","article-title":"The influence of T cell Ig mucin-3 signaling on central nervous system autoimmune disease is determined by the effector function of the pathogenic T cells","volume":"190","author":"Lee","year":"2013","journal-title":"J. Immunol."},{"key":"2025032404213723500_r35","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ni1271","article-title":"The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity","volume":"6","author":"Zhu","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032404213723500_r36","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1084\/jem.20081398","article-title":"Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection","volume":"205","author":"Jones","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032404213723500_r37","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1093\/infdis\/jiq153","article-title":"Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection","volume":"203","author":"Abdelbary","year":"2011","journal-title":"J. Infect. Dis."},{"key":"2025032404213723500_r38","doi-asserted-by":"crossref","first-page":"14733","DOI":"10.1073\/pnas.1009731107","article-title":"Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection","volume":"107","author":"Jin","year":"2010","journal-title":"Proc. Natl. Acad. Sci. 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