Frias, Adolfo
(2020)
Transcriptional and translational regulators: Roles in development and function of innate-like and adaptive regulatory T cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Invariant natural killer T (iNKT) cells and regulatory T cells (Tregs) both have roles in maintaining immune homeostasis. However, following disease, these cells often undergo loss of function and reduction in cell frequency. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes capable of rapidly producing cytokines post-stimulation with the potent iNKT cell activator α-Galactosylceramide (α-GalCer). We investigated the function of microRNAs (miRNAs) in iNKT cells, which are translational regulators that can quickly modulate regulation of protein synthesis. While miRNAs have been described in the development of iNKT cell development, no miRNAs had been ascribed to their effector function. We investigated whether microRNA-155 (miR-155) played a role in regulating the effector function of iNKT cells, as it was already shown to do so in CD8+ T cells and NK cells. Although we verified that miR-155 was upregulated in iNKT cells post α-GalCer stimulation, we found that miR-155 deficiency did not have an impact on iNKT cell cytokine production. Considering iNKT cells regulatory functions in maintaining immune homeostasis, miR-155 could be a potential therapeutic target to disrupt effector function in other immune cells while maintaining the effector function in iNKT cells.
We also investigated the role of the transcriptional regulator Id2 in adipose-resident Tregs (aTregs). Inhibitor of DNA binding (Id) proteins are transcriptional regulators that dimerize with E protein transcription factors to inhibit their binding to E box sites and thus, prevent their activity. We verified that Id2 was upregulated in aTregs compared to higher Id3 expression in splenic Tregs. Under standard diet, loss of Id2 in aTregs led to a phenotype seen in high-fat-diet fed mice including a decrease in frequency and canonical aTreg markers including ST2, CCR2, KLRG1, and GATA3. Additionally, Id2 deficiency in Tregs led to increased systemic inflammation and impaired glucose tolerance. In essence Id2 expression was necessary for the aTreg transcriptional program including regulation of aTreg function to mediate tissue homeostasis. In summary, this thesis helps illuminate the unique influence of transcriptional and translational regulation on aTreg and iNKT cells which is critical for immune homeostasis.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
6 April 2020 |
| Date Type: |
Publication |
| Defense Date: |
4 September 2019 |
| Approval Date: |
6 April 2020 |
| Submission Date: |
11 March 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
122 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
immunology, tissue homeostasis, transcriptional regulation, visceral adipose tissue, glucose tolerance |
| Date Deposited: |
06 Apr 2020 18:51 |
| Last Modified: |
06 Apr 2020 18:51 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38300 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}