Date of Award

12-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbiology, Immunology, and Biochemistry

Research Advisor

Terrence L. Geiger, Ph.D., M.D

Committee

Hongbo Chi, Ph.D. Elizabeth A. Fitzpatrick, Ph.D. Thirumala-Devi Kanneganti, Ph.D. Tony N. Mario, Ph.D.

Keywords

autoimmunity, EAE, high-throughput sequencing, public TCR repertoire, Treg

Abstract

The major histocompatibility complex (MHC) is the strongest genetic risk factor for autoimmunity. It acts together with a corresponding TCR repertoire, yet, considering the extent of the repertoire's diversity, how this imposes disease susceptibility on a population is not well understood. We address the hypothesis that shared or public TCR, those present in most individuals, modulate autoimmune risk. High resolution analyses of autoimmune encephalomyelitis-associated T-cell receptor β chain (TCRβ) showed preferential utilization of public TCR sequences, implicating them in pathogenesis. Disease-associated public TCRβ, when transgenically expressed in association with endogenously rearranged T-cell receptor α chain (TCRα), could further endow unprimed T cells with autoantigen reactivity. Enforced expression of two of six public but no private TCRβ further provoked spontaneous, early-onset autoimmunity in mice. These findings implicate public TCR in skewing repertoire response characteristics and autoimmune susceptibility, demonstrate how single TCR chains can bias autoantigen specificity, and suggest that subsets of public TCR sequences may serve as diseasespecific biomarkers or therapeutic targets.

DOI

10.21007/etd.cghs.2014.0381

Comments

Six month embargo expired June 2015

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