Mechanisms of CD8 T Cell-mediated Control of Mouse Polyomavirus and the Requirement for Naïve T Cell Recruitment to Maintain Immunologic Memory Öffentlichkeit

Abstract

Mechanisms of CD8 T Cell-mediated Control of Mouse Polyomavirus and the Requirement for Naïve T Cell Recruitment to Maintain Immunologic Memory

Human polyomaviruses (PyV) have plagued immune-deficient patients who develop PyV associated pathology due to the lack of anti-polyomavirus agents and host determinants predicting susceptibility to disease. The mouse polyomavirus (MPyV) model allows the study of the immunologic control of the virus in its natural host. CD8+ T cells recognizing infected cells are required for viral control and tumor resistance. However, usual mechanisms needed to clear intracellular pathogens (TNF-α, Fas, perforin) were dispensable for MPyV control. Work in human PyVs found IFN-γ can inhibit PyV replication. Against MPyV, IFN-γ treatment in vitro reduced MPyV gene expression and viral replication in a dose-dependent manner. Mice lacking the IFN-γ receptor (IFN-γR-/-) maintain functional CD8+ T cells, yet fail to control MPyV in vivo, displaying increased viral loads and susceptibility to MPyV-tumors. IFN-γR-/- transplanted kidneys harbor increased viral burden compared to normal wild-type (WT) kidney transplants. Finally, IFN-γ provided therapeutic viral control during persistent MPyV infection in the kidney, a reservoir of persistent mouse and human polyomaviruses. This demonstrates IFN-γ is an anti-polyomavirus agent with therapeutic potential.

Due to the dynamics involved with antigen and inflammation during chronic viral infections, it is unknown if memory developed against PyV resembles that against latent chronic pathogens. We have found that persistently infected mice maintain a large, stable anti-viral CD8 response, yet these memory cells are short lived upon transfer to naïve mice. Interestingly, new naïve progenitors can be primed de novo, contributing to the memory T cell pool. Therefore, we developed a novel MPyV TCR transgenic system that allows the monitoring of the timing of priming and how this affects the pool of memory T cells. Late MPyV-infection recruited CD8 T cells were stably maintained, possessing improved phenotype, multi-cytokine functionality, and superior recall potential. In contrast, acute-infection recruited cells were deleted over time, and displayed characteristics of exhaustion. This indicates CD8 T cells recruited during persistent MPyV infection contribute significantly to the preservation of functional memory against MPyV.

Table of Contents

Table of Contents
Abstract
List of Figures
Chapter I: Introduction 1

I. Adaptive immunity to viral infections 1
II. CD8 T cell Responses 6
III. The generation and role of CD8 T cell memory? 9
IV. CD8 T cell memory perturbations during persistent infections 16
V. Polyomaviruses as a tool to study low level persistent infections 22

Chapter 2: IFN-γ controls mouse polyomavirus infection in vivo 58
Chapter 3: CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion 101

Chapter 4: Discussion 148
Chapter II

Figure 1: IFN-γ has anti-MPyV activity in vitro 86
Figure 2: Effect of IFN-γ on growth and death of MPyV-infected cells 87
Figure 3: IFN-γR-/- mice have reduced ability to control MPyV infection in the kidney 88
Figure 4: IFN-γR-/- mice maintain a functional MPyV-specific CD8+ T cell response 89
Figure 5: Impaired control of MPyV infection in IFN-γR-/- kidney transplants 90
Figure 6: IFN-γ administration during persistent MPyV infection reduces virus levels 91
Sup Fig 1: MPyV-HA visualized by flow cytometry and IHC 92
Sup Fig 2: IFN-γ reduces MPyV protein expression on a per cell basis 93

Chapter III

Figure 1: Distinct response profiles for virus-specific CD8 T cells recruited during acute and persistent MPyV infection 133
Figure 2: Expression of memory markers by CD8 T cells differs with timing of recruitment during MPyV infection 134
Figure 3: Minimal changes in memory phenotype of acute infection-recruited anti-MPyV CD8 T cells over long-term maintenance 135
Figure 4: Persistent infection-recruited memory CD8 T cells express higher multi-cytokine functionality and reduced Blimp-1 136
Figure 5: Acute MPyV infection-recruited CD8 T cells suffer exhaustion 137
Figure 6: CD4 T cells are required for maintenance of memory MPyV-specific CD8 T cells during persistent infection 138
Figure 7: MPyV-specific CD8 T cells recruited in persistent, but not acute, infection mount recall responses 139
Sup Fig 1: MPyV.LT206 infects B6 mice equivalently to wild type MPyV.A2 and specifically stimulates TCR-I CD8 T cells 140
Sup Fig 2: Polyclonal MPyV-specific CD8 T cells recruited during persistent infection express canonical memory markers 141

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology Biology, Cell
Stichwort	CD4 T cell IFNg Exhaustion Persistent Infection MPyV Memory CD8 T cell interferon gamma Anti-viral polyomavirus
Committee Chair / Thesis Advisor	Lukacher, Aron E, Emory University
Committee Members	Evavold, Brian, Emory University Selvaraj, Periasamy, Emory University Williams, Ifor, Emory University Newell, Kenneth, Emory University Zimring, James C, Emory University

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