Differentiation pathway of virus-specific stem-like CD8+ T cells during chronic infection Open Access

Abstract

T cell exhaustion is a characteristic feature of chronic viral infection and cancer. Exhausted CD8+ T cells are marked by the expression of negative regulatory surface proteins and progressive loss of effector function. Targeting checkpoint molecules expressed on exhausted CD8+ T cells restores their proliferative capacity, cytotoxicity, and cytokine production. These molecules, such as PD-1 pathway inhibitors, are successful at treating many cancer types; however, not all tumor types are susceptible nor do all patients with these tumors respond. Two major obstacles to improving immunotherapy are the co-expression of multiple inhibitory proteins on the surface of exhausted CD8+ T cells and the heterogeneity present within the antigen-specific CD8+ T cell pool in chronic viral infection and cancer. In the mouse lymphocytic choriomeningitis virus model of chronic infection, two antigen-specific CD8+ T cell populations have been identified: a PD-1 + Tcf-1 + stem-like subset capable of self-renewal and differentiation into a second, more terminally-differentiated PD-1 + Tim3+ effector-like population. These Tcf-1 + stem-like CD8+ T cells have now been found in a variety of chronic viral infections and human tumors. Here, we perform RNA-sequencing to comprehensively identify the repertoire of cell surface molecules expressed by these two exhausted CD8+ T cell populations. We find that expression of CD101 divides PD-1 + Tim3+ CD8+ T cells into two distinct populations. Using adoptive transfer experiments, we show that the stem-like Tcf-1 + CD8+ T cells initially differentiate into a transitory population of CD101- Tim3+ cells that later irreversibly convert into CD101+ Tim3+ cells. CD101+ Tim3+ CD8+ T cells are transcriptionally distinct from both stemlike and CD101- Tim3+ transitory cells, including altered expression of transcription factors and high levels of many checkpoint molecules. In contrast, recently-generated CD101- Tim3+ cells show a distinct, effector-like transcriptional signature and are more functional than the terminally differentiated CD101+ Tim3+ cells. PD-1 pathway blockade increases the numbers of these newly-generated CD101- Tim3+ CD8+ T cells, suggesting that these transitory and more functional cells may play a critical role in PD-1 based immunotherapy.

Table of Contents

Introduction 1

Methods 4

Results 10

Discussion 27

Future Directions 30

Conclusion 32

References 34

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Bioinformatics Biology, Cell Biology, Virology
Keyword	RNA-sequencing LCMV CD8+ T cells immunotherapy PD-1 immunology exhaustion
Committee Chair / Thesis Advisor	Rafi Ahmed, Emory University
Committee Members	Haydn T. Kissick, Emory University Arri Eisen, Emory University William H. Hudson, Emory University

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