Counter-Regulation of Human Cd4+ T Helper 2 Lymphocyte Development and Stability by Type I Interferon

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dc.contributor.advisorFarrar, J. Daviden
dc.creatorHuber, Jonathan Philipen
dc.date.accessioned2013-01-16T21:07:34Z
dc.date.issued2013-01-16
dc.description.abstractInnate cytokines shape the differentiation of CD4+ T cells from naïve precursors into multiple functional subsets in order carry out effective adaptive immune responses to diverse immunological stimuli. Interleukin-12 controls the development of T helper 1 (Th1) cells, which fight infection by intracellular pathogens such as bacteria and viruses. Helminth parasites and allergens induce the production of IL-4, which drives differentiation to Th2. The IL-12 and IL-4 signaling pathways also counter-regulate each other, though this balance favors Th2 as IL-4 signaling overrides the effects of IL-12. In addition, IL-4 induces expression of the GATA3 transcription factor that stabilizes the Th2 phenotype through auto-regulatory maintenance of its own expression. A role for type I interferon (IFN-α/β), a major antiviral cytokine, has been described more recently in Th1 cells, but the potential role of IFN-α/β in counter-regulating Th2 development is poorly understood. My work reveals that IFN-α/β blocks IL-4-induced Th2 differentiation of human CD4+ T cells by inhibiting expression of GATA3. The loss of GATA3 in developing Th2 cells leads to reduced secretion of the Th2 cytokines, IL-4, IL-5, and IL-13, and reduced expression of chemoattractant receptor expressed in Th2 cells (CRTh2). IFN-α/β also suppresses GATA3 in committed Th2 cells, leading to a loss of the Th2 phenotype. GATA3 transcription utilizes two distinct first exons, exon 1A and 1B, which are controlled by separate promoters, but IL-4 signaling in Th2 cells leads to preferential utilization of the upstream exon 1A transcript. IFN-α specifically blocks expression of the 1A but not 1B transcript, indicating a specific regulation of Th2 cells. Furthermore, IFN-α appears to induce epigenetic silencing of an upstream conserved non-coding sequence I, which may be required for optimal exon 1A transcription in Th2 cells. This work reveals an unexpected role for IFN-α in selectively inhibiting Th2 but not Th1 differentiation, which may be important for ensuring appropriate development of antiviral immunity. In addition, the ability of IFN-α to suppress both developing Th2 cells and previously committed Th2 cells suggests that IFN-α may be useful as a novel therapeutic for atopic diseases.en
dc.identifier.oclc828671914
dc.identifier.urihttps://hdl.handle.net/2152.5/1218
dc.language.isoenen
dc.subjectInterferon-alphaen
dc.subjectInterferon-betaen
dc.subjectT-Lymphocytesen
dc.titleCounter-Regulation of Human Cd4+ T Helper 2 Lymphocyte Development and Stability by Type I Interferonen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2014-12-21
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineImmunologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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