CD4 T helper (Th) cells differentiate into distinct effector or regulatory subsets as needed during the course of an infection. Ikaros is a transcription factor that is necessary for proper thymic T cell development. In order to study the role of Ikaros in peripheral CD4 T-cell differentiation and function, a novel Ikaros conditional knockout mouse in which Ikaros is deleted in mature T-cells (CKO mice) was developed. In this thesis, this model is characterized and used to evaluated how absence of Ikaros affects lymphocyte and myeloid populations in vivo, and CD4 T-cell differentiation into T helper 17 (Th17) and inducible regulatory T cell (iTreg) subsets in vitro. CKO mice had normal thymocyte development and normal percentages of T-cells and B-cells in the spleen. However, they had increased percentages of myeloid cells, and an abnormal population of "naive-like" CD4 T-cells that expressed low levels of CD62L and CD44, markers that identify naive and memory T cell populations. CKO CD4 T-cells cultured under Th17 polarizing conditions showed normal expression of the Th17 factors, RORγt and IL-17A, but overexpressed the pro-inflammatory factors T-bet, IFNγ and GM-CSF. CKO CD4 T-cells had a decreased ability to become iTregs as shown by significantly less Foxp3+ CD4+ T-cells in polarizing cultures, and overexpress T-bet, IFNγ and GM-CSF. Therefore, T-cells that lack Ikaros do not properly differentiate into either Th17 or iTreg lineages, but instead become cells with altered pro-inflammatory characteristics. In conclusion, the data highlights new roles of Ikaros in maintaining proper CD4 T-cell populations in the periphery and in suppressing abnormal pro-inflammatory responses.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/23813 |
| Date | 13 July 2017 |
| Creators | Lyon De Ana, Carolina |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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