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Permanent link (DOI): https://doi.org/10.7939/R3ZS2KQ2N

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Mechanisms underlying lymphopenia-driven autoimmunity in the setting of co-inhibitory molecule deficiency Open Access

Descriptions

Other title
Subject/Keyword
Autoimmunity
Tolerance
Co-stimulation
Co-inhibition
Lymphopenia
T cell receptor
TCR
PD-1
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Ellestad, Kristofor K
Supervisor and department
Anderson, Colin (Surgery)
Examining committee member and department
Baldwin, Troy (Medical Microbiology and Immunology)
Ostergaard, Hanne (Medical Microbiology and Immunology)
Lacy, Paige (Medicine)
Hazes, Bart (Medical Microbiology and Immunology)
Zeng, Defu (Department of Diabetes Immunology, Beckman Research Institute, Duarte, CA)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2016-09-19T15:26:51Z
Graduation date
2016-06:Fall 2016
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
T lymphocytes (T cells) are powerful directors and effectors of immunity. The system of pseudo-random rearrangements of the T cell receptor (TCR) loci that underlie their ability to recognize a vast universe of molecular patterns is at once useful and dangerous, because many T cells develop TCR that can recognize self, and while most developing T cells with high affinity for self are removed from the repertoire during thymic development, the process is not perfect and some dangerous clones escape. These newly generated T cells have only passed through one “filtration” process in the thymus, and therefore peripheral tolerance mechanisms are critical in order to avoid autoimmunity. Homeostasis of T cells in the periphery is tightly regulated by competition for a finite resource pool, including homeostatic cytokines and relevant peptide:MHC (pMHC) complexes with which a T cell can interact and receive at least a “tonic” or greater signal. In conditions of lymphopenia, which can arise as a consequence of viral infections, clinical interventions, and other stimuli, resources are in excess and T cells will undergo a process of lymphopenia-induced proliferation (LIP) to fill their available niche. Importantly, LIP is strongly associated with inflammatory disease. The co-inhibitory receptor programmed death-1 (PD-1) is expressed on T cells where it provides inhibitory signals that help prevent inappropriate T cell activation or keep T cells in an unresponsive state. PD-1-/- mice are predisposed to infrequent and mild autoimmunity. In contrast, reconstitution of the lymphoid compartment of lymphopenic adult Rag-/- mice with PD-1-/- hematopoietic stem cells (HSC) gives rise to a rapid and severe systemic autoimmune disease shortly after the first newly generated T cells emerge from the thymus. Thus a “three strikes” combination of newly generated T cells, deficiency of PD-1, and LIP synergizes to promote autoimmunity. Our goal herein was to explore the mechanisms and cells underlying the disease in this model. One of PD-1’s ligands, PD-L1, has been associated with the generation of peripheral FoxP3+ regulatory T cells (pTreg), which are critical mediators of immune tolerance. Also, while PD-1 is known to be up-regulated following conventional T cell activation, we hypothesized that PD-1 might control the comparatively weak “tonic” signals T cells receive in response to self pMHC, and in the setting of LIP of newly generated T cells, this lack of restraint on normally tonic signals led to a widespread self pMHC-directed polyclonal response. We examined the role of PD-1 in the control of pTreg generation and found that deficiency of PD-1 does not preclude pTreg generation or regulatory T cell function. Instead, PD-1 is important for restraining the expansion of both conventional and regulatory cells in a lymphopenic host, suggesting that clinical approaches to tumour immunotherapy mediated by PD-1 blockade are unlikely to work by inhibiting tumour-associated pTreg generation and may actually expand them. We also found that PD-1 indeed controls LIP of T cells in response to tonic pMHC signals, and thus PD-1-/- T cells out-expanded WT cells in competitive in vivo assay in an MHC-dependent manner but independent of signals from the IL-7 receptor. Using a model system where we could purify newly generated T cells from the periphery of an adult, lymphoreplete mouse, we found that these cells were not rapidly tolerized upon contact with the periphery but instead maintained their autoimmune-generating potential for a period of time. Mice lacking MHC Class II expression were spared from autoimmunity, suggesting that CD4+ T cells are the main effectors of disease in the PD-1-/- HSC model. Furthermore, disease was not dependent on either of two canonical T cell killing mechanisms, the Perforin-Granzyme B pathway or the Fas/FasL pathway. Together these data may suggest that disease in our model is driven by a cytokine storm, and beyond advancing our basic understanding of how co-inhibitors control homeostasis of T cells, this model may be useful for developing approaches to treat diseases associated with cytokinemias, such as graft-versus-host disease or immune reconstitution inflammatory syndrome in human immunodeficiency virus patients.
Language
English
DOI
doi:10.7939/R3ZS2KQ2N
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Ellestad KK, Thangavelu G, Ewen CL, Boon L, Anderson CC. PD-1 is not required for natural or peripherally induced regulatory T cells: Severe autoimmunity despite normal production of regulatory T cells. European Journal of Immunology. 2014;44(12):3560–3572.

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