Year: 2018
Type: dissertation
Abstract: IL-17-producing γδ T (γδT17) cells are critical components of the innate immune system, and serve as an early and important source of IL-17 in host protective immune responses and autoimmunity. The complexity of the pathways that drive the development and functional programming of γδ T cells has become increasingly evident in recent years, yet they remain poorly understood. This thesis focuses on the gene network that drives the development of a fetal-derived subset of γδT17 cells which populates various lymphoid and mucosal tissues in mice. I have identified a newly defined subset of CD24-CD73- γδT17 cells, which are comprised primarily of fetal-derived Vγ6+ and Vγ4+ RORγt+ γδ T cells. I found that a functional bifurcation occurs at the CD24+CD73- stage, which then resolves in a Vγ-chain specific manner. RORγt- Vγ5 and Vγ1 cells develop along CD24+CD73+ and CD24-CD73+ stages to become γδT1s, and RORγt+ Vγ6 and Vγ4 cells directly downregulate CD24 to become CD24-CD73- γδT17 cells. I showed that HEB (Tcf12) is required for the generation of these CD73- γδT17 cells. HEB is required in the immature CD24+CD73- γδ T cells for the expression of Sox4, Sox13, and Rorc, and these genes are repressed by acute expression of the HEB antagonist Id3. I further demonstrated that HEB can directly regulate Sox4 and Sox13 transcription. HEB-deficiency also impacts mature CD73+ γδ T cells, which are defective in RORγt expression and IL-17 production. Additionally, the fetal HEB-/- Vγ chain repertoire is altered, and peripheral Vγ4 γδ T cells are largely restricted to the IFNγ-producing phenotype. Therefore, I have identified several HEB-dependent pathways for the development of CD73+ and CD73- γδT17 cells, and provided mechanistic evidence for the control of the γδT17 gene network by HEB.
Source: TSpace (University of Toronto)
Author: Seung Hyun In
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3152715395