Manipulation of Immune Regulatory Mechanisms During Chronic Infection Open Access

Penaloza, Pablo Andres (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/3n203z351?locale=en
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Abstract

Chronic infections affect millions of people worldwide, and herald significant decline in economic growth. A factor that contributes to the establishment of a persistent infection is the progressive dysfunction that takes place on antigen-specific T cells. A major focus in the field of immunology is the rescue of epitope-specific T cells by blocking or triggering specific receptors on the surface of immune cells. Here we analyze the contribution of different immune regulatory pathways during chronic viral infection in mice. We also show a role for CD4+ Foxp3+ T regulatory (Treg) cells in maintaining CD8 T cell exhaustion during chronic infection. Collectively, our data suggests that Treg-mediated suppression is dependent on antigen abundance, CD4 cells, and the B7 pathway. These findings show that immune regulatory pathways could be manipulated during chronic viral infection in order to rescue T cell function.

Table of Contents

Table of Contents

Table of Contents
Table of Figures

Chapter 1: Introduction
Chronic viral Infections and T cel exhaustion...1
Regulation of immune responses: Role of T regulatory cel s during homeostasis
and immune responses...9

Chapter 2: CD137 signaling synergizes with PD-L1 blockade to augment
CD8 T cell responses during chronic viral infection

Abstract...15
Introduction...17
Materials and Methods...20
Results...22
Discussion...29
Figures...34

Chapter 3: Opposing effects of CD70 costimulation during acute and
chronic viral infection

Abstract...40

Introduction...42
Materials and Methods...45
Results...47
Discussion...51
Figures...56

Chapter 4: Enhancing the T Cell restorative effect of PD-L1 blockade by
depletion of CD4 cells

Abstract...63
Introduction...64
Materials and Methods...66
Results...67
Discussion...69
Figures...72

Chapter 5: T regulatory cells sustain CD8 T cell exhaustion during chronic
infection

Abstract...79
Introduction...80
Materials and Methods...83
Results...85

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