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

Li, Weiyan (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/hm50tr904?locale=en
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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

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