Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Joshi, Nikhil

Abstract

CD8 T cells are an integral part of the immune system, principally responsible for the cytolytic clearance of virally infected and cancerous cells. They adapt to the nature of the immune response they are partaking in by adopting distinct cell fates through a process of highly coordinated differentiation. These fates are characterized by the activation and suppression of functional programs under the control of transcription factors and epigenetic machinery, which integrate cell extrinsic signals to drive differentiation. Here we elucidate the function of a group of transcription factors in dictating CD8 T cell differentiation in infection. We go on to characterize one specific factor of interest, KLF2, which we find has the unique role of maintaining lineage fidelity along the differentiation trajectory of effector and memory CD8 T cells. We find KLF2 not only regulates T cell trafficking as has been previously described but also contributes to cell fate decisions through the suppression of the exhaustion promoting factor TOX and enablement of effector defining factors such as TBET. Finally, we characterize a critical role for KLF2 in maintaining stem-like CD8 T cells in the context of tumors and tumor draining lymph nodes, thereby supporting the anti-tumor immune response and potentiating memory and effector function.

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