The Role of PD-1 in regulating CD8 T cell response in LCMV infection Público

Li, Weiyan (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/hm50tr904?locale=pt-BR
Published

Abstract

Chronic infections such as human immunodeficiency virus (HIV), human hepatitis B virus (HBV) and human hepatitis C virus (HCV) afflict more than 500 million people worldwide. Functionally impaired (exahusted) antigen-specific CD8 T cell is a hallmark of many chronic infections including the HIV HBV and HCV, and also a major cause leading to the failure of the host in antigen clearance. Programmed death-1 (PD-1) is highly expressed on exhausted T cells and is an inhibitory receptor for T cell receptor signaling. Manipulation of PD-1 inhibitory signal has been shown to have great therapeutic potential in vaccine design and chronic disease treatment.

In this study I utilized a PD-1 deficient (PD-1-/- ) P14 transgenic mouse model in conjunction with chronic and acute lymphocytic choriomeningitis virus (LCMV) infection to investigate the role of PD-1 in regulating antigen-specific CD8 T cell response. During chronic LCMV infection, PD-1-/- P14 CD8 T cells peaked at a higher frequency. However, an exaggerated contraction followed this increase and resulted in an overall decrease of antigen-specific CD8 T cell number. In contrast to the dramatic kinetics change in chronic infection, PD-1-/- antigen-specific CD8 T cells in an acute LCMV infection behaved similarly compared to wild type controls. However, a gradual loss in PD-1-/- CD8 T cells was observed during later memory phase, revealing a defect in memory CD8 T cell differentiation and survival within the PD-1-/- antigen-specific CD8 T cell population.

My work has examined antigen-specific CD8 T cell response in the absence of PD-1 signaling under physiologic conditions. Novel findings in cell number kinetics demonstrated that complete loss of PD-1-mediated inhibition is detrimental to T cell survival in both acute and chronic LCMV infection, with an earlier and more severe effect seen in chronic LCMV infection. PD-1 signaling has been a key target for artificial interference to optimize immune response. My studies provide important information for numerous PD-1 based strategies in vaccine design, chronic disease treatment and tumor immunotherapy.

Table of Contents

Introduction...1
PD-1 and its ligands...2
Structure and expression profile...2
PD-1: PD-L pathway in autoimmunity and peripheral tolerance...4
PD-1: PD-L pathway in immunopathology...6
PD-1: PD-L signaling pathway in T cells...7
Memory CD8 T cells in viral infection...10
LCMV infection...11
Memory CD8 T cell differentiation in acute infection...12
CD8 T cells in chronic viral infection...16
Materials & Methods...18
General experiment outline...18
Mice...18
Infections...19
Generation of chimeric mice...19
Tissue collection and single cell suspension preparation...20
Surface & Intracellular staining...22
Ex vivo stimulation assay...23
Flow Cytometry...23
Statistic Analysis...24
Results...25
Overview...25
PD-1-/- P14 CD8 T cells in chronic LCMV infection...25
PD-1-/- P14 CD8 T cells during acute LCMV infection...40
Discussion...43
References...48

About this Master's Thesis

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research Field
Palavra-chave
Committee Chair / Thesis Advisor
Committee Members
Última modificação

Primary PDF

Supplemental Files