Reference - Detail
|Author||Kamimura D, Bevan MJ.|
|Title||Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection.|
The transcription factor X-box-binding protein-1 (XBP-1) plays an essential role in activating the unfolded protein response in the endoplasmic reticulum (ER). Transcribed XBP-1 mRNA is converted to its active form by unconventional cytoplasmic splicing mediated by inositol-requiring enzyme-1 (IRE-1) upon ER stress. We report activation of the IRE-1/XBP-1 pathway in effector CD8(+) T cells during the response to acute infection. Transcription of unspliced XBP-1 mRNA is up-regulated by IL-2 signals, while its splicing is induced after TCR ligation. Splicing of XBP-1 mRNA was evident during the expansion of Ag-specific CD8(+) T cells in response to viral or bacterial infection. An XBP-1 splicing reporter revealed that splicing activity was enriched in terminal effector cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1). Overexpression of the spliced form of XBP-1 in CD8(+) T cells enhanced KLRG1 expression during infection, whereas XBP-1(-/-) CD8(+) T cells or cells expressing a dominant-negative form of XBP-1 showed a decreased proportion of KLRG1(high) effector cells. These results suggest that, in the response to pathogen, activation of ER stress sensors and XBP-1 splicing contribute to the differentiation of end-stage effector CD8(+) T cells.
|MeSH||Acute Disease Animals Antigens, Bacterial / genetics Antigens, Bacterial / immunology Antigens, Bacterial / metabolism CD8-Positive T-Lymphocytes / immunology* CD8-Positive T-Lymphocytes / metabolism Cell Differentiation / genetics Cell Differentiation / immunology* DNA-Binding Proteins / biosynthesis DNA-Binding Proteins / genetics DNA-Binding Proteins / immunology* Endoplasmic Reticulum / genetics Endoplasmic Reticulum / immunology Endoplasmic Reticulum / metabolism Listeria monocytogenes / immunology Listeriosis / genetics Listeriosis / immunology* Listeriosis / metabolism Membrane Proteins / genetics Membrane Proteins / immunology Membrane Proteins / metabolism Mice Mice, Knockout Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / immunology Protein-Serine-Threonine Kinases / metabolism RNA Splicing / genetics RNA Splicing / immunology* RNA, Messenger / biosynthesis RNA, Messenger / genetics RNA, Messenger / immunology* Receptors, Immunologic / biosynthesis Receptors, Immunologic / genetics Receptors, Immunologic / immunology Regulatory Factor X Transcription Factors Signal Transduction / genetics Signal Transduction / immunology Transcription Factors / biosynthesis Transcription Factors / genetics Transcription Factors / immunology* Up-Regulation / genetics Up-Regulation / immunology X-Box Binding Protein 1|