Ikaros is a transcription factor expressed in blood cells. Germline Ikaros mutations yield abnormal T cells due to defects in T cell maturation. Therefore, to study the role of Ikaros in mature CD4+ T cells, a conditional knockout mouse was developed such that Ikaros is expressed until CD4+ T cells have matured. Ikaros-deficient CD4+ T cells from these mice have a phenotype which is associated with inflammatory diseases and autoimmunity. In experiments described in this thesis, I show that lack of Ikaros in CD4+ T cells results in the upregulation of type I interferon (IFN)-induced gene programs. Upregulation in interferon sensitive genes (ISGs) is not due to environmental cues since α/β receptor (IFNAR1) signaling pathways are not activated. In addition, the phenotype is localized to CD4+ T cells containing the Ikaros mutation, as increased ISG expression is not observed in macrophages. Enhanced ISG expression also impairs the ability of Ikaros-deficient CD4+ T cells to be infected with virus. In addition, the Ikaros conditional knockout mice showed an increased population of CD11b+ T cells in the spleen, which may be related to the increase in ISG expression, as cells with this phenotype arise during viral infection when type I IFN expression would be high. Furthermore, we were able to obtain human Jurkat cell lines with CRISPR engineered Ikaros knockouts. However, I was unable to confirm that Ikaros was successfully knocked out in these cell lines. Taken together, these data demonstrate a role for Ikaros in the repression of type I IFN gene programs, which are critical for preventing and fighting viral infections, and also play a role in autoimmunity. Ikaros may also play a role in the regulation of CD11b+ T cell populations, which remains to be explored.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36541 |
| Date | 12 June 2019 |
| Creators | Derosia, Nicole |
| Contributors | Winandy, Susan, Kiley, Debra |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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