CD8 T cell Differentiation during Acute and Chronic Viral Infection Open Access
McManus, Daniel (Fall 2024)
Abstract
How CD8 T cells develop during acute versus chronic antigen exposure is central to understanding immunity during viral infections, cancer, and autoimmunity. Stem-like CD8 T cells are specialized progenitor cells that maintain the CD8 T cell response in these contexts. Here, we examined the generation, fate, and plasticity of these cells during acute and chronic viral infection. We find that nearly identical populations of stem-like CD8 T cells arise early after acute and chronic infection. This indicates that the generation of stem-like CD8 T cells occurs agnostic to infection outcome, ensuring that the host is prepared in advance for a potential long-term infection. In both acute and chronic infection, the transcription factor TOX was required for the generation of stem-like CD8 T cells, and continuous antigen exposure was required for their maintenance. We next performed reciprocal adoptive transfer experiments to track the fate of early stem-like CD8 T cells during viral clearance versus persistence, and to examine the impact that infection origin has on their differentiation potential. When transferred into an acute, resolving infection, early stem-like CD8 T cells from chronic infection converted into memory cells, enriched for properties of central memory CD8 T cells. When transferred into mice harboring a life-long infection, early stem-like CD8 T cells from acute infection performed as chronic resource cells. They expanded vigorously, giving rise to stem-like, effector, and terminally differentiated CD8 T cells. For over a month, they maintained the CD8 T cell response in lymphoid and non-lymphoid tissues, becoming quiescent as the infection reached the late/established phase. They even responded to PD-1 blockade, providing a proliferative burst equal to that of the virus-specific endogenous CD8 T cell response. Altogether, we show that stem-like CD8 T cells are generated early during viral infection and can adapt their differentiation trajectory based on infection outcome. They become memory CD8 T cells if the virus is rapidly cleared, or chronic resource cells if the virus persists. These findings raise new questions on the potential importance of stem-like CD8 T cells for immunological memory and re-emphasize the essential role that they play during chronic viral infection. Lastly, this work provides further insight into the early differentiation events that enable the CD8 T cell response to adapt to acute or chronic viral infection.
Table of Contents
List of Figures 7
Chapter 1: Introduction 10
Preamble 10
LCMV as a model system for studying CD8 T cells 11
1. Structure, genome, and life cycle
2. Acute and chronic LCMV infection in mice
The anti-viral CD8 T cell response 13
1. Activation
2. CD8 T cell response during acute viral infection: expansion, contraction, memory
3. CD8 T cell response during chronic viral infection: exhaustion
4. CD8 T cell differetniation pathway during chronic viral infection
Chapter 2: Early fate and anatomical commitment of stem-like CD8 T cells 21
Abstract
Introduction
Results/Discussion
Materials and Methods
Chapter 3: Development of stem-like CD8+ T cells during chronic infection 39
Abstract
Introduction
Results
Discussion
Materials and Methods
Chapter 4: The stem-like CD8 T cell fate decision is agnostic to 61
infection outcome
Abstract
Introduction
Results
Discussion
Materials and Methods
Chapter 5: Fate of stem-like CD8 T cells in acute and chronic viral 92
infection
Abstract
Introduction
Results
Discussion
Materials and Methods
Chapter 6: Discussion 126
References 134
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