Indiana University-Purdue University Indianapolis (IUPUI) / CD4 T cells are critical regulators of inflammatory diseases and play an important
role in allergic airway diseases (AAD) by producing type 2 cytokines including IL-4, IL-
13, IL-5 and IL-9. In chronic AAD models, IL-9 producing CD4 T-helper (TH9) cells lead
to accumulation of eosinophils and mast cells in the airway, increase levels of type-2
cytokines, stimulate ILC2 cell proliferation, and induce mucus production from airway
epithelium. However, the transcriptional network that governs the development of TH9
cells and their function during allergic responses is not clearly understood. Naïve CD4 T
cells differentiate into TH9 cells in the presence of IL-2, IL-4 and TGFβ, activating a
complex network of transcription factors that restricts their development to TH9 lineage. In
this study a variety of approaches were utilized, including characterizing Il9 reporter mice,
to identify an additional Ets-transcription factor termed ERG (Ets-related gene) that
is expressed preferentially in the TH9 subset. Knock-down of Erg during TH9 polarization
led to a decrease in IL-9 production in TH9 cells in vitro. Deletion of Erg at the later stage
of TH9 induced pathogenesis resulted in reduced IL-9 production in the airways in chronic
AAD. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9
promoter region is restricted to the TH9 lineage and is sustained during TH9 polarization.
In the absence of PU.1 and ETV5, ERG regulated IL-9 production independent of other
Ets-transcription factors and the deletion of Erg further lead to a decrease in IL-9
production by lung-derived CD4-T cells in chronic AAD model. Lastly, I also identified
IL-9 secreting CD4 tissue resident memory cell population that play an instrumental role in allergic recall responses. In summary, in this study novel transcription factors were
identified that can regulate TH9 function and the role of IL-9 in allergic airway recall
responses. / 2022-12-28
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/27248 |
| Date | 12 1900 |
| Creators | Kharwadkar, Rakshin Prashant |
| Contributors | Kaplan, Mark H., Harrington, Maureen, Mosley, Amber, Janga, Sarath, Zhou, Baohua |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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