Nieves-Rosado, Hector M.
(2024)
Tim-3+ Treg control viral persistence and effector T cell responses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Tim-3, a surface protein, is upregulated on Treg during chronic viral infections. However, the role of regulatory T cells (Treg) during persistent viral infections has not been fully defined. We hypothesize that Tim-3 promotes an effector phenotype on Treg during chronic viral infection, which limits the virus-specific T cell response and impairs viral clearance. First, we used flow cytometry to evaluate the immunosuppressive phenotype and signaling pathways in peripheral Tim-3- versus Tim-3+ Treg in people with HIV on antiretroviral therapy (PWH-ART). Tim-3+ Treg showed an increased expression of IL-10 compared to persons without HIV-1 (PWOH), and elevated phosphorylation signaling relative to Tim-3- Treg in PWH-ART. Tim-3 blockade restrained the in vitro suppressive capacity of peripheral Treg. Therefore, our data demonstrate that Tim-3 contributes directly to the enhanced suppressive activity of Treg in this setting. For the second part of this project, we employed an inducible Treg-specific Tim-3 loss-of-function (Tim-3 Treg KO) murine model to dissect the role of Tim-3 on Treg during LCMV chronic viral infection. We found a significant decrease in morbidity, a more potent virus-specific T cell response, and a significant decrease in viral burden. Tim-3 Treg KO mice exhibited a decrease in the frequency of PD-1+Tim-3+ and PD-1+Tox+ LCMV-specific CD8 T cells. Our findings demonstrate that modulation of a single surface protein in Treg can lead to a reduction in viral burden, limit T cell exhaustion, and enhance LCMV-specific T cell response. These studies may help to identify Tim-3-directed therapies for the management of persistent infections and other chronic illnesses.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
21 August 2023 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
25 August 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
144 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
n/a |
| Date Deposited: |
16 Sep 2024 18:52 |
| Last Modified: |
16 Sep 2024 18:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45364 |
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