Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

E. John Wherry

Abstract

Adaptive immune cells play key roles in antiviral and antitumor responses, and CD8 T cells are the central cell types during these processes. In different immunological conditions(e.g. vaccination) and disease settings, CD8 T cells perform distinct differentiation paths into effector, memory and exhausted T cells. Transcription factors(TF) play key roles in the cell fate decision, and dissecting transcriptional control of CD8 T cell responses provides the key mechanisms of how CD8 T cells differentiate toward specific cell fates. During my graduate school study, I have done four major questions related to CD8 T cell transcriptional control: 1) How does memory CD8 T cells(TMEM cells) survive? I have found that c-Myb is the key TF to control TMEM cell survival molecule Bcl-2/Bcl-XL, and c-Myb level is controlled by a microRNA, miR-150(Chen and Stelekati, et al., Cell Reports, 2017, Chapter 2); 2) What happens to canonical terminal effector T cells(TEFF cells) during chronic infection and cancer? I have found that chronic TEFF-like cells get diminished during chronic infection and restrained by master TF TCF-1(Chen and Ji, et al., Immunity, 2019, Chapter 3); 3) How does exhausted T cells(TEX cells) survive during chronic infection? I have found that TCF-1-centralled TF network, including c-Myb and Eomes as TCF-1 downstream targets, contributes to the TEX precursor generation and survival(Chen and Ji, et al., Immunity, 2019,, Chapter 3); 4) How to generate robust TEFF-like response during chronic infection or cancer? I have established an optimized T cell in vivo CRISPR screening system. Using this system, I found TF Fli1 restrains T cell proliferation and TEFF differentiation during both acute and chronic infection, and Fli1-deficient CD8 T cells skew from TMEM or TEX toward a robust TEFF cell fate, leading to better anti-infection or anti-tumor responses(Chen et al.,bioRxiv/SSRN, 2020, Chapter 4). By answering these questions, we now have a more complete and better understanding of CD8 T cell responses during chronic infections and cancer, and hope these transcriptional mechanisms can help to improve T cell related immune therapies for better clinical outcomes.

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