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Transcriptional and translational regulators: Roles in development and function of innate-like and adaptive regulatory T cells

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 (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Frias, Adolfoadf44@pitt.eduadf44@pitt.edu0000-0001-5768-3568
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorD'Cruz,
Committee ChairKane,
Committee MemberDelgoffe,
Committee MemberMorelli,
Committee MemberWilliams,
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


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