Egr-2 and PD-1 Are Required for Induction and Maintenance of T Cell Anergy: A Dissertation
Bishop, Kenneth D.
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Keywords
DNA-Binding Proteins
Transcription Factors
Zinc Fingers
Antigens
Surface
CD4-Positive T-Lymphocytes
Diabetes Mellitus
Type 1
Islets of Langerhans Transplantation
Immune Tolerance
Immunosuppression
Amino Acids, Peptides, and Proteins
Biological Factors
Cells
Endocrine System Diseases
Genetic Phenomena
Hemic and Immune Systems
Immune System Diseases
Nutritional and Metabolic Diseases
Surgical Procedures, Operative
Therapeutics
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Abstract
The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.