3 results on '"Thabet Y"'
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2. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection.
- Author
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Beyer M, Abdullah Z, Chemnitz JM, Maisel D, Sander J, Lehmann C, Thabet Y, Shinde PV, Schmidleithner L, Köhne M, Trebicka J, Schierwagen R, Hofmann A, Popov A, Lang KS, Oxenius A, Buch T, Kurts C, Heikenwalder M, Fätkenheuer G, Lang PA, Hartmann P, Knolle PA, and Schultze JL
- Subjects
- Adolescent, Adult, Aged, Animals, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Flow Cytometry, HEK293 Cells, HIV physiology, HIV Infections genetics, HIV Infections virology, Host-Pathogen Interactions immunology, Humans, Immunoblotting, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus physiology, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Oligonucleotide Array Sequence Analysis, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor immunology, Receptors, Tumor Necrosis Factor metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcriptome drug effects, Transcriptome genetics, Transcriptome immunology, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha pharmacology, Young Adult, CD4-Positive T-Lymphocytes immunology, HIV immunology, HIV Infections immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Tumor Necrosis Factor-alpha immunology
- Abstract
Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.
- Published
- 2016
- Full Text
- View/download PDF
3. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.
- Author
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Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K, Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, Schönfeld EA, Böttcher J, Golovina T, Mayer CT, Hofmann A, Sommer D, Debey-Pascher S, Endl E, Limmer A, Hippen KL, Blazar BR, Balderas R, Quast T, Waha A, Mayer G, Famulok M, Knolle PA, Wickenhauser C, Kolanus W, Schermer B, Bluestone JA, Barry SC, Sparwasser T, Riley JL, and Schultze JL
- Subjects
- 3' Untranslated Regions genetics, 3' Untranslated Regions immunology, Animals, Cell Differentiation drug effects, Chromatin Assembly and Disassembly drug effects, Flow Cytometry, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Gene Expression Profiling, Genome, Human, Genome-Wide Association Study, Humans, Lentivirus, Lymphocyte Activation drug effects, Matrix Attachment Region Binding Proteins genetics, Matrix Attachment Region Binding Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs immunology, MicroRNAs metabolism, MicroRNAs pharmacology, RNA Interference, RNA, Small Interfering immunology, RNA, Small Interfering metabolism, RNA, Small Interfering pharmacology, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory metabolism, Transduction, Genetic, Chromatin Assembly and Disassembly immunology, Forkhead Transcription Factors immunology, Gene Expression Regulation, Matrix Attachment Region Binding Proteins immunology, Self Tolerance drug effects, Self Tolerance genetics, Self Tolerance immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.
- Published
- 2011
- Full Text
- View/download PDF
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