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Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection
Journal article   Open access   Peer reviewed

Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection

Jacob V Gorman, Gabriel Starbeck-Miller, Nhat-Long L Pham, Geri L Traver, Paul B Rothman, John T Harty and John D Colgan
The Journal of immunology (1950), Vol.192(7), pp.3133-3142
04/01/2014
DOI: 10.4049/jimmunol.1302290
PMCID: PMC3965639
PMID: 24567532
url
http://doi.org/10.4049/jimmunol.1302290View
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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.
 Flow Cytometry Tumor Necrosis Factor-alpha - metabolism Cell Proliferation CD8-Positive T-Lymphocytes - transplantation Receptors, Virus - metabolism Cell Survival - genetics Adoptive Transfer Interferon-gamma - metabolism Listeria monocytogenes - immunology Receptors, Virus - genetics Host-Pathogen Interactions - immunology Listeriosis - immunology Tumor Necrosis Factor-alpha - immunology CD8-Positive T-Lymphocytes - metabolism Receptors, Antigen, T-Cell - immunology Listeria monocytogenes - physiology Receptors, Antigen, T-Cell - metabolism Mice, Inbred C57BL Mice, Transgenic Cell Survival - immunology Hepatitis A Virus Cellular Receptor 2 Mice, Knockout Animals Interferon-gamma - immunology Receptors, Virus - immunology Listeriosis - microbiology Mice Mice, Congenic Receptors, Antigen, T-Cell - genetics CD8-Positive T-Lymphocytes - immunology

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