GSBS Dissertations and Theses

ORCID ID

0000-0002-5307-6776

Publication Date

2019-06-14

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Program in Molecular Medicine

First Thesis Advisor

Katherine Luzuriaga

Keywords

Epstein-Barr virus, EBV, acute infectious mononucleosis, T-cell receptor, TCR, T cell, CD8 T cell, CDR3, TCR repertoire, TCR sequencing, BRLF1, BMLF1

Abstract

Epstein-Barr Virus (EBV) is a ubiquitous human virus linked to several diseases, including cancers. CD8 T cells are important for controlling EBV replication. Generation and maintenance of virus-specific CD8 T cells is dependent on specific interaction between MHC-peptide complexes on the infected cell and the CD8 T cell receptor (TCR). Several lines of evidence suggest that the TCR repertoire is an essential component of the CD8 T-cell immune response. The current work focuses on delineating the features of the TCR repertoire that drive the selection of EBV-specific CD8 T cells into the memory phase. We used bulk and single-cell TCRαβ sequencing to analyze the TCR repertoire of human CD8 T cells specific for two immunodominant HLA-A02:01-restricted EBV-derived epitopes: BRLF1109-117 (YVLDHLIVV) and BMLF1280-288 (GLCTLVAML) during the acute and memory phases of primary EBV infection in humans. We showed that persistent EBV-specific clonotypes accounted for only 9% of unique clonotypes but were highly expanded in acute EBV infection and more commonly expressed identifiable features than non-persistent clonotypes. The other 91% of highly diverse unique clonotypes disappeared and were replaced in convalescence by equally diverse “de-novo” clonotypes. We provide evidence suggesting that recognition of BRLF1109-117may be driven by the TCRα. We identified a highly dominant and degenerate BRLF1109-117-specific TCRα sequence, AV8.1-CAVKDTDKLIF-AJ34, that was shared by all donors studied and identified conserved residues within this sequence that were important for antigen recognition. These findings are relevant to current efforts to develop or optimize the efficacy of T cell based therapies or vaccines.

DOI

10.13028/b4jm-8160

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Saturday, July 24, 2021

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