Regulation of T cell responses by microRNAs Öffentlichkeit

Abstract

Understanding the mechanisms underlying the generation of effector functions and immune memory by T cells is essential to the development of more effective vaccination strategies. Various molecular pathways involved in effector and memory T cell development have been elucidated over the last few decades. However, how translational regulation mechanisms are involved in this process is less clear. MicroRNAs play a major role in translational regulation. My dissertation research focuses on how microRNAs govern the differentiation of T cells during the immune response to viral infection. In the first study, I demonstrate that the miR-17-92 cluster is highly expressed in proliferating effector CD8 T cells. miR-17-92 enhances mTOR signaling and promotes CD8 T cell clonal expansion through enhancing proliferation. However, excessive levels of miR-17-92 drive effector CD8 T cells into terminal differentiation and result in compromised memory CD8 T cell development. In my second study, I investigate how miR-17-92 regulates the antiviral immune response mediated by CD4 T cells. Similar to what is seen in CD8 T cells, miR-17-92 is necessary for the clonal expansion of CD4 T cells after viral infection. The generation of IFN-γ-producing CD4 T cells is especially sensitive to the level of miR-17-92 expression. In addition, miR-17-92 over-expression preferentially expands the Th1 response, which indicates that different subsets of effector CD4 T cells are differentially regulated by miR-17-92. Interestingly, virus-specific CD4 T cells that over-express miR-17-92 are not terminally differentiated and can generate a normal memory compartment. Thus, these studies provide insight into how microRNAs are involved in the differentiation of virus-specific T cells and highlight the importance of translational regulation in the immune response to viral infection.

Table of Contents

Chapter 1: Introduction....................................................................................................... 1

Part I: Immunity and the immune system....................................................................... 1

Part II: CD8 T cell responses during viral infection........................................................ 1

Part III: Follicular helper T cells.................................................................................... 18

Part IV: microRNA....................................................................................................... 27

Part V: Significance....................................................................................................... 37

Chapter 2: Temporal expression of microRNA cluster miR-17-92 regulates effector and memory CD8⁺ T-cell differentiation............................................................................................................... 39

Abstract......................................................................................................................... 40

Introduction................................................................................................................... 40

Results........................................................................................................................... 43

Discussion...................................................................................................................... 51

Materials and Methods.................................................................................................. 54

Acknowledgements....................................................................................................... 54

Supporting Information................................................................................................. 54

Chapter 3: miR-17-92 regulates CD4 T cell differentiation during antiviral immune responses 79

Abstract......................................................................................................................... 80

Introduction................................................................................................................... 80

Materials and methods.................................................................................................. 83

Results........................................................................................................................... 85

Discussion...................................................................................................................... 92

Chapter 4: Conclusion and Future Directions................................................................. 109

BIBLIOGRAPHY.......................................................................................................... 115

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Biochemistry, Cell & Developmental Biology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Molecular Health Sciences, Immunology Biology, Cell
Stichwort	miR-17-92 microRNA follicular helper T cell CD8 T cell immune memory effector T cell
Committee Chair / Thesis Advisor	Ahmed, Rafi, Emory University
Committee Members	Boss, Jeremy, Emory University Cheng, Xiaodong, Emory University Fu, Haian, Emory University Moreno, Carlos S, Emory University

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