Intrinsic Mechanisms Regulating T Cell Tolerance in Autoimmune Diabetes

Zhang, Qianxia (2018) Intrinsic Mechanisms Regulating T Cell Tolerance in Autoimmune Diabetes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Type 1 Diabetes (T1D) is a polygenic autoimmune disease characterized by immune cell infiltration into the islets of Langerhans, destruction of insulin-producing cells, and uncontrolled hyperglycemia. Islet-antigen reactive CD4+ and CD8+ T cells, and regulatory T cells (Tregs) are the major players in T1D pathogenesis. Both cell-intrinsic and cell-extrinsic inhibitory mechanisms are required to maintain self-tolerance to islet-antigens.
Lymphocyte Activation Gene 3 (LAG3, CD223), a co-inhibitory receptor highly expressed on T cells, is one of these essential mechanisms that intrinsically regulate T cell tolerance in autoimmune diabetes. I evaluate the role of LAG3 on T cells versus non-T cells, CD8+ T cells, and Tregs by generating mice in which LAG3 is specifically absent on these subsets in a murine model of T1D. In Chapter 3, I show that the predominant expression of LAG3 on insulitic CD4+ and CD8+ T cells is required to limit the pathogenesis of autoimmune diabetes in non-obese diabetic (NOD) mice. The loss of LAG3 on CD8+ T cells alone is sufficient to promote early onset of autoimmune diabetes by promoting islet-specific glucose-6-phophatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells to differentiate into effector T cells. In Chapter 4, I show that LAG3 is preferentially and constitutively expressed on a subset of insulitic Tregs, and loss of LAG3 on Tregs leads to delayed onset and reduced incidence of autoimmune diabetes. LAG3 may intrinsically limit Treg proliferation and functionality by repressing pathways that promote the maintenance of Tregs in the pancreas of NOD mice.
In addition to dissecting the role of LAG3 in regulating T cell tolerance, I also show that removal of programmed death protein 1 (PD1) or overexpression of Neuropilin 1 (Nrp1) on Tregs protect NOD mice from autoimmune diabetes in Appendix A and Appendix B, respectively. In summary, my findings have advanced our understanding of cell-intrinsic mechanisms that regulate T cell tolerance in autoimmune diabetes.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Zhang, Qianxia qsz1@pitt.edu qsz1 0000-0002-2885-2147
ETD Committee:	Title Member Email Address Pitt Username ORCID Thesis Advisor Vignali, Dario dvignali@pitt.edu Committee Chair Vignali, Dario dvignali@pitt.edu Committee Member Gaffen, Sarah sarah.gaffen@pitt.edu Committee Member Kane, Lawrence lkane@pitt.edu Committee Member Lucas, Peter lucaspc@upmc.edu Committee Member Piganelli, Jon jdp51@pitt.edu Committee Member Shlomchik, Mark MSHLOMCH@pitt.edu
Date:	22 February 2018
Date Type:	Publication
Defense Date:	11 January 2018
Approval Date:	22 February 2018
Submission Date:	20 February 2018
Access Restriction:	3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages:	170
Institution:	University of Pittsburgh
Schools and Programs:	School of Medicine > Immunology
Degree:	PhD - Doctor of Philosophy
Thesis Type:	Doctoral Dissertation
Refereed:	Yes
Uncontrolled Keywords:	Autoimmunity, Type 1 Diabetes, LAG3, T Cell Tolerance, Regulatory T cells, Autoreactive T cells
Related URLs:	Publication "LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes" Publication "Co-stimulatory and Co-inhibitory Pathways in Autoimmunity"
Date Deposited:	22 Feb 2018 15:37
Last Modified:	22 Feb 2021 06:15
URI:	http://d-scholarship.pitt.edu/id/eprint/33800

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