{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/4200"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/4200","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Type I Interferon Mediates Th2 Reprogramming and Acute Suppression of Effector Functions","abstract":"The type I interferon (IFN-α/β) family is a pleiotropic set of cytokines that play a role in regulating many biological functions, including suppressing viral replication and modulating adaptive immune functions. Although IFN-α/β has been extensively studied regarding the activation of interferon sensitive genes, much less is known regarding its role as a negative regulator. Here, I demonstrate a role for IFN-α/β in the regulation of Th2 development as well as memory Th2 cell function. The Th2 master transcription factor GATA3, promotes its own expression through a positive regulatory loop, uncoupling the cell from the requirement of IL-4 signaling. IFN-α/β inhibits this process by inducing epigenetic modifications within the GATA3 locus that prevent this positive regulatory loop from being established. Reduced DNase hypersensitivity and enhanced H3K27me3 correlates with a reduction in GATA3 gene expression by targeting the IL-4-sensitive alternative transcript exon 1a for suppression. These results demonstrate that IFN-α/β interferes with IL-4-mediated programming and induction of GATA3 through the enhancement of gene-silencing histone modifications within the GATA locus. In addition to mediating chromatin modifications required for the long-term suppression of genes, IFN-α/β signaling also acutely suppresses gene expression in pre-committed Th2 cells. Here, I demonstrate the cellular and molecular pathways involved in suppressing the TCR-mediated expression of the human IL5 gene. IFN-α treatment potently suppressed IL5 and IL13 gene expression by reducing the rate of nascent transcription, independent of de novo expression of ISGs. Further, I show that IFN-α-mediated STAT4 activation is required to suppress gene expression. Furthermore, IFN-α/β-mediated acute suppression occurs in a species-specific manner, since murine Th2 cells are not regulated by IFN-α/β signaling in contrast to human Th2 cells. This robust suppression of acute IL5 and IL13 expression, paired with the suppression of Th2 development, provide further evidence that IFN-α/β is a candidate for the treatment of allergic disease.","abstract_html":"The type I interferon (IFN-α/β) family is a pleiotropic set of cytokines that play a role in regulating many biological functions, including suppressing viral replication and modulating adaptive immune functions. Although IFN-α/β has been extensively studied regarding the activation of interferon sensitive genes, much less is known regarding its role as a negative regulator. Here, I demonstrate a role for IFN-α/β in the regulation of Th2 development as well as memory Th2 cell function. The Th2 master transcription factor GATA3, promotes its own expression through a positive regulatory loop, uncoupling the cell from the requirement of IL-4 signaling. IFN-α/β inhibits this process by inducing epigenetic modifications within the GATA3 locus that prevent this positive regulatory loop from being established. Reduced DNase hypersensitivity and enhanced H3K27me3 correlates with a reduction in GATA3 gene expression by targeting the IL-4-sensitive alternative transcript exon 1a for suppression. These results demonstrate that IFN-α/β interferes with IL-4-mediated programming and induction of GATA3 through the enhancement of gene-silencing histone modifications within the GATA locus. In addition to mediating chromatin modifications required for the long-term suppression of genes, IFN-α/β signaling also acutely suppresses gene expression in pre-committed Th2 cells. Here, I demonstrate the cellular and molecular pathways involved in suppressing the TCR-mediated expression of the human IL5 gene. IFN-α treatment potently suppressed IL5 and IL13 gene expression by reducing the rate of nascent transcription, independent of de novo expression of ISGs. Further, I show that IFN-α-mediated STAT4 activation is required to suppress gene expression. Furthermore, IFN-α/β-mediated acute suppression occurs in a species-specific manner, since murine Th2 cells are not regulated by IFN-α/β signaling in contrast to human Th2 cells. This robust suppression of acute IL5 and IL13 expression, paired with the suppression of Th2 development, provide further evidence that IFN-α/β is a candidate for the treatment of allergic disease.","abstract_has_math":false,"creators":["Gonzales-van Horn, Sarah Ruth"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Niederkorn, Jerry Y.","Farrar, J. David","D'Orso, Iván","Gill, Michelle A.","van Oers, Nicolai S. C."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-09-05T14:50:09Z","date_published":"2017-09-05T14:50:09Z","updated_at":"2026-07-24T05:52:06Z","subjects":["DNA Methylation","GATA3 Transcription Factor","Interferon-alpha","Signal Transduction","Th2 Cells","Transcription, Genetic"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1002857180"],"render_values":[{"text":"1002857180","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/4200","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Niederkorn, Jerry Y.","Farrar, J. David","D'Orso, Iván","Gill, Michelle A.","van Oers, Nicolai S. 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Although IFN-α/β has been extensively studied regarding the activation of interferon sensitive genes, much less is known regarding its role as a negative regulator. Here, I demonstrate a role for IFN-α/β in the regulation of Th2 development as well as memory Th2 cell function. The Th2 master transcription factor GATA3, promotes its own expression through a positive regulatory loop, uncoupling the cell from the requirement of IL-4 signaling. IFN-α/β inhibits this process by inducing epigenetic modifications within the GATA3 locus that prevent this positive regulatory loop from being established. Reduced DNase hypersensitivity and enhanced H3K27me3 correlates with a reduction in GATA3 gene expression by targeting the IL-4-sensitive alternative transcript exon 1a for suppression. These results demonstrate that IFN-α/β interferes with IL-4-mediated programming and induction of GATA3 through the enhancement of gene-silencing histone modifications within the GATA locus. In addition to mediating chromatin modifications required for the long-term suppression of genes, IFN-α/β signaling also acutely suppresses gene expression in pre-committed Th2 cells. Here, I demonstrate the cellular and molecular pathways involved in suppressing the TCR-mediated expression of the human IL5 gene. IFN-α treatment potently suppressed IL5 and IL13 gene expression by reducing the rate of nascent transcription, independent of de novo expression of ISGs. Further, I show that IFN-α-mediated STAT4 activation is required to suppress gene expression. Furthermore, IFN-α/β-mediated acute suppression occurs in a species-specific manner, since murine Th2 cells are not regulated by IFN-α/β signaling in contrast to human Th2 cells. This robust suppression of acute IL5 and IL13 expression, paired with the suppression of Th2 development, provide further evidence that IFN-α/β is a candidate for the treatment of allergic disease."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Type I Interferon Mediates Th2 Reprogramming and Acute Suppression of Effector Functions"]}]}],"canonical_facts":{"dc:contributor":["Niederkorn, Jerry Y.","Farrar, J. David","D'Orso, Iván","Gill, Michelle A.","van Oers, Nicolai S. C."],"dc:creator":["Gonzales-van Horn, Sarah Ruth"],"dc:date":["2017-09-05T14:50:09Z","2015-08","2015-05-22","August 2015","2017-09-05T14:43:25Z"],"dc:description":["The type I interferon (IFN-α/β) family is a pleiotropic set of cytokines that play a role in regulating many biological functions, including suppressing viral replication and modulating adaptive immune functions. Although IFN-α/β has been extensively studied regarding the activation of interferon sensitive genes, much less is known regarding its role as a negative regulator. Here, I demonstrate a role for IFN-α/β in the regulation of Th2 development as well as memory Th2 cell function. The Th2 master transcription factor GATA3, promotes its own expression through a positive regulatory loop, uncoupling the cell from the requirement of IL-4 signaling. IFN-α/β inhibits this process by inducing epigenetic modifications within the GATA3 locus that prevent this positive regulatory loop from being established. Reduced DNase hypersensitivity and enhanced H3K27me3 correlates with a reduction in GATA3 gene expression by targeting the IL-4-sensitive alternative transcript exon 1a for suppression. These results demonstrate that IFN-α/β interferes with IL-4-mediated programming and induction of GATA3 through the enhancement of gene-silencing histone modifications within the GATA locus. In addition to mediating chromatin modifications required for the long-term suppression of genes, IFN-α/β signaling also acutely suppresses gene expression in pre-committed Th2 cells. Here, I demonstrate the cellular and molecular pathways involved in suppressing the TCR-mediated expression of the human IL5 gene. IFN-α treatment potently suppressed IL5 and IL13 gene expression by reducing the rate of nascent transcription, independent of de novo expression of ISGs. Further, I show that IFN-α-mediated STAT4 activation is required to suppress gene expression. Furthermore, IFN-α/β-mediated acute suppression occurs in a species-specific manner, since murine Th2 cells are not regulated by IFN-α/β signaling in contrast to human Th2 cells. This robust suppression of acute IL5 and IL13 expression, paired with the suppression of Th2 development, provide further evidence that IFN-α/β is a candidate for the treatment of allergic disease."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/4200","1002857180"],"dc:language":["en"],"dc:subject":["DNA Methylation","GATA3 Transcription Factor","Interferon-alpha","Signal Transduction","Th2 Cells","Transcription, Genetic"],"dc:title":["Type I Interferon Mediates Th2 Reprogramming and Acute Suppression of Effector Functions"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:06Z"}