Regulation of Effector and Memory Development of Human CD4+ T Cells by Interleukin 12 and Type I Interferon
| dc.contributor.advisor | Farrar, J. David | en |
| dc.creator | Davis, Ann Marie | en |
| dc.date.accessioned | 2010-07-12T18:43:15Z | |
| dc.date.available | 2010-07-12T18:43:15Z | |
| dc.date.issued | 2009-01-09 | |
| dc.description.abstract | Innate cytokines induced at the onset of infection regulate the development of adaptive immune responses such as CD4+ T helper cell development. For instance, the innate cytokines interleukin 12 (IL-12) and type I interferon (IFN-alpha/beta) are produced in response to intracellular bacterial and viral infections. While the effects of IL-12 on CD4+ T cell differentiation are relatively well-understood, the role of IFN-alpha/beta, despite extensive study, has remained controversial. The present work seeks to clarify the effects of IFN-alpha/beta on CD4+ T cell development, effector functions, and memory generation. Previous reports had suggested that IFN-alpha, like IL-12, could promote Th1 development in human CD4+ T cells. However, my work demonstrates that IFN-alpha is insufficient to induce Th1 differentiation because of an inability to maintain stable STAT4 phosphorylation or T-bet expression. Furthermore, IL-12, but not IFN-alpha, induces the secretion of IFN-gamma and TNF-alpha from human CD4+ T cells. These two cytokines, in addition to promoting bacterial clearance, can directly participate in antiviral immunity via a signaling pathway which involves the type I IFN receptor. Finally, a combination of IL-12 and IFN-alpha influences memory CD4+ T cell function by strongly inducing IL-2 secretion from a subset of cells in a T-bet-independent manner. These IL-2-producing cells demonstrate both phenotypic and functional characteristics of long-lived and pluripotent central memory. Taken together, these data provide a new understanding of the role of innate cytokines in shaping adaptive CD4+ T cell responses. Given the numerous medical uses of IFN-alpha/beta, these findings could have a broad impact on the design of vaccines and antiviral therapeutics. | en |
| dc.format.digitalOrigin | born digital | en |
| dc.format.medium | Electronic | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 759853519 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/645 | |
| dc.language.iso | en | en |
| dc.subject | CD4-Positive T-Lymphocytes | en |
| dc.subject | Immunologic Memory | en |
| dc.subject | Interferon-alpha | en |
| dc.title | Regulation of Effector and Memory Development of Human CD4+ T Cells by Interleukin 12 and Type I Interferon | en |
| dc.type | Thesis | en |
| dc.type.genre | dissertation | en |
| dc.type.material | Text | en |
| thesis.date.available | 2010-01-09 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Immunology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |