title: Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection.
abstract: 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-γ production and degranulation by Tim-3 KO cells stimulated with peptide Ag ex vivo. To address the T cell-intrinsic 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.
authors.affiliation: Interdisciplinary Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Gorman
authors.forename: Gabriel
authors.initials: G
authors.lastname: Starbeck-Miller
authors.forename: Nhat-Long L
authors.initials: NL
authors.lastname: Pham
authors.forename: Geri L
authors.initials: GL
authors.lastname: Traver
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.forename: John D
authors.initials: JD
authors.lastname: Colgan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D000072597:Hepatitis A Virus Cellular Receptor 2; D054884:Host-Pathogen Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology* / Q000502:physiology; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma