Exploration Of Exhausted Cd8+ T Cell Subset Diversity During Chronic Viral Infection And Cancer: A Role For Gfi1

Authors

Oluwagbemiga Abiodun Ojo, University of Alabama at Birmingham

Advisory Committee Chair

Robert Welner

Advisory Committee Members

Allan Zajac

Andre Ballesteros-Tato

Christopher Willey

Jianmei Leavenworth

Lewis Shi

Document Type

Dissertation

Date of Award

1-1-2025

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Continued persistence of high antigen levels in chronic viral infection and tumor settings induces molecular adaptations in CD8+ T cells that has been termed dysfunction or exhaustion. Although exhausted cells exhibit profound loss of effector functions, the exacerbated viral titer and tumor burden in the absence of these cells highlights their crucial role in maintaining the balance between tissue pathology and antigen clearance. Exhausted CD8+ T cells are a heterogeneous pool with unique functions that contribute to virus or tumor control. Yet, we lack a complete understanding of the subset dynamics as the disease develops. Here, we provide detailed characterization of CD8+ T cells during exhaustion. Using a chronic viral infection model, we identify a previously undescribed population of Transitional Ly108+CX3CR1+ cells in addition to the progenitor, effector-like and terminally-exhausted cells that were previously described. We show that Transitional cells are the direct precursors of the exhausted effector-like and terminally-exhausted cells. During tumorigenesis, we discovered that early infiltrating CD8+ T cells are progenitor cells that differentiate into Tim3hiTbetlo and Tim3hiTbethi effector cells. The Tim3+ cells differentially express the transcription factors Eomes and Tox that promote exhaustion and are associated with response to inhibitory receptor blockade. Analysis of exhausted CD8+ T cells identified the transcriptional repressor Gfi1 as a regulator of subset dynamics during exhaustion. Gfi1 expression is reduced as progenitors differentiate into Transitional cells. Differentiation from Transitional cells into the effector-like or terminally-exhausted subset required re-expression of Gfi1. Similarly, we show that differentiation from the Gfi1hi progenitors is associated with reduction in Gfi1 levels; however, its expression was required for terminal differentiation and accumulation of Tim-3hi cells. Overall, the data presented provide a novel role for Gfi1 in the diversification of CD8+ T cell subsets that mediate chronic viral infection and tumor control. These studies provide a better basis for understanding exhausted CD8+ T cell subset development.

Comments

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Recommended Citation

Ojo, Oluwagbemiga Abiodun, "Exploration Of Exhausted Cd8+ T Cell Subset Diversity During Chronic Viral Infection And Cancer: A Role For Gfi1" (2025). All ETDs from UAB. 6880.
https://digitalcommons.library.uab.edu/etd-collection/6880