Yano, Hiroshi
(2020)
Regulatory T cell-derived inhibitory cytokines and regulation of anti-tumor immunity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Regulatory T cells (Tregs) play a crucial role in the maintenance of self-tolerance and prevent overt immune responses during infection. One of the primary mechanisms of immune regulation by Tregs is via secretion of inhibitory cytokines (IL-10, IL-35, and TGF-β), and activated Tregs producing these inhibitory cytokines are highly enriched in the tumor microenvironment (TME). However, it is yet unclear whether intratumoral Tregs preferentially utilize one regulatory mechanism over others in the TME. We have previously demonstrated that Treg-derived IL-35 regulate anti-tumor immunity by promoting the inhibitory receptor expression in CD8+ TILs.
As induction of a dysfunctional state known as T cell exhaustion in tumor-infiltrating T cells presents a barrier to effective cancer immunotherapy, it is imperative to understand the mechanism of Treg-derived inhibitory cytokine-mediated induction of T cell exhaustion and the developmental relationship between subpopulations of effector Tregs in the TME. In Chapter 3, I demonstrate that IL-10+ and IL-35+ Tregs are not distinct, stable subsets of Tregs, and intratumoral Tregs exhibit the environmentally inducible adaptive plasticity of the IL-10 and IL-35 expression. In Chapter 4, I show that Treg-derived IL-10 and IL-35, despite the difference in their receptors and the downstream signal transduction, commonly target the BLIMP1-IR axis in CD8+ T cells to directly promote a dysfunctional state of T cells. Furthermore, in Chapter 5, I present an alternative function of Treg-derived Ebi3 that is independent of the IL-12 cytokine family and a novel cytokine complex composed of IL-10 and Ebi3 produced by activated Tregs. Treg-derived Ebi3 may have a broader physiological role than previously appreciated, and a comprehensive understanding of such unconventional role of Ebi3 in modulating immune responses is crucial to develop a novel therapeutic approach to target Ebi3 rationally.
In addition to my thesis study, Appendix A lists the publications that I have contributed, as well as additional academic achievements such as awards and honors received at external conferences.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
5 January 2020 |
| Date Type: |
Publication |
| Defense Date: |
15 November 2019 |
| Approval Date: |
5 January 2020 |
| Submission Date: |
4 December 2019 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
291 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
How the immune system self-regulates negatively to impede recognition and destruction of malignant cancer. |
| Date Deposited: |
06 Jan 2020 03:08 |
| Last Modified: |
05 Jan 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37944 |
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