title: Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion.
abstract: T cell exhaustion is thought to be a natural mechanism for limiting immune pathology, although it may be desirable to circumvent this mechanism to help eliminate viral reservoirs or tumors. Although there are no definitive markers, a fingerprint for exhausted T cells has been described that includes the transmembrane proteins PD-1, LAG3, and Tim-3. However, apart from the recruitment of tyrosine phosphatases to PD-1, little is known about the biochemical mechanisms by which these proteins contribute to the development or maintenance of exhaustion. Tim-3 contains no known motifs for the recruitment of inhibitory phosphatases, but it may actually increase signaling downstream of TCR/CD3, at least under acute conditions. Other studies showed that T cell exhaustion results from chronic stimulation that extends the effector phase of T cell activation, at the expense of T cell memory. We suggest that Tim-3 may contribute to T cell exhaustion by enhancing TCR-signaling pathways.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and Cancer Immunology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Cancer Immunology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Cancer Immunology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 lkane@pitt.edu.
authors.forename: Lawrence P
authors.identifier: http://orcid.org/0000-0001-5198-516X
authors.initials: LP
authors.lastname: Kane
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D015497:HIV-1 / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D000074462:Positive Regulatory Domain I-Binding Factor 1; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000093322:Lymphocyte Activation Gene 3 Protein
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