Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Regulatory T cell-derived inhibitory cytokines and regulation of anti-tumor immunity

Yano, Hiroshi (2020) Regulatory T cell-derived inhibitory cytokines and regulation of anti-tumor immunity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Restricted to University of Pittsburgh users only until 5 January 2022.

Download (75MB) | Request a Copy

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.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Yano, Hiroshihiy12@pitt.eduhiy120000-0002-3098-2629
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVignali, Dariodvignali@pitt.edu
Committee ChairWilliams, Johnjvw@chp.edu
Committee MemberDelgoffe, Gregdelgoffeg@upmc.edu
Committee MemberTurnquist, Hethhet5@pitt.edu
Committee MemberPoholek, Amandapoholeka@pitt.edu
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: 06 Jan 2020 03:08
URI: http://d-scholarship.pitt.edu/id/eprint/37944

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item