Abstract
Tight regulation of virus-induced cytotoxic effector CD8(+) T cells is essential to prevent immunopathology. Naturally occurring effector CD8(+) T cells, with a KLRG1(hi) CD62L(lo) phenotype typical of short-lived effector CD8(+) T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquin(san)), effector CD8(+) T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8(+) T cell homeostasis and prevent CD8-mediated autoimmunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / transplantation
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Cell Aggregation / genetics
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Cell Aggregation / immunology*
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Cellular Senescence / genetics
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Cellular Senescence / immunology
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Cytotoxicity, Immunologic* / genetics
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Homeostasis / genetics
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Homeostasis / immunology
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Immunosuppressive Agents / antagonists & inhibitors
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Immunosuppressive Agents / metabolism
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics*
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Lectins, C-Type / biosynthesis
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Lectins, C-Type / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mutation / immunology
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RNA Stability / immunology
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RNA, Messenger / antagonists & inhibitors*
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RNA, Messenger / genetics
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Receptors, Immunologic
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Ubiquitin-Protein Ligases / genetics
Substances
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Immunosuppressive Agents
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KLRG1 protein, human
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Lectins, C-Type
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RNA, Messenger
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Receptors, Immunologic
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Trans-Activators
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Interferon-gamma
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Rc3h1 protein, mouse
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Ubiquitin-Protein Ligases