The novel roles of BCL6 and BATF3 in regulating human
CD8⁺ T cell dysfunction
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Traunbauer-aktraun-phd-biology-2025-thesis .pdf
Description
Thesis PDF
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22.37 MB
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330e40869fe46adfc5c0f4aabc60a556
Author(s)
Traunbauer, Anna Katharina
Advisor(s)
Walker, Bruce D.
Date Issued
September 2025
Publisher
Massachusetts Institute of Technology
Abstract
Reduced effector function and elevated inhibitory receptor expression are hallmarks of exhausted CD8⁺ T cells, yet the underlying molecular and epigenetic drivers remain incompletely defined. Here, we developed an in vitro repeated stimulation model to recapitulate features of human CD8⁺ T cell dysfunction and delineate transcriptional and epigenetic landscapes. Our analyses revealed that BCL6 and BATF3 are robustly upregulated in dysfunctional CD8⁺ T cells, with ATAC-seq demonstrating enhanced chromatin accessibility at their gene loci. Transcription factor footprinting shows increased BATF3 motif occupancy in chronically stimulated cells and integrative multi-omic analysis combining footprints, open chromatin regions, RNA-seq and ChIP-seq data revealed that putative BATF3 target genes may include master regulators of exhaustion. Moreover, overexpression of BCL6 or BATF3 markedly upregulates TIM-3 expression and suppressed cytokine release, establishing their capacity to induce T cell dysfunction. We further validated these findings ex vivo in antigen-specific CD8⁺ T cells from patients with advanced melanoma, as well as HCV and HIV infections, where cells were enriched for BCL6^high and BATF3^high subsets co-expressing canonical exhaustion markers such as PD-1, TIM-3 and CD39. Notably, Single-cell RNA sequencing of HIV-specific CD8⁺ T cells identified a distinct BCL6^high PD1⁻ progenitor population that gives rise to two distinct subsets via divergent differentiation trajectories: one branch generates effector-like BCL6^high PD1⁺ cells, whereas the other produces BCL6^high PD1⁺ cells that retain an exhaustion gene signature alongside partial memory-like feature. Collectively, these findings identify BCL6 and BATF3 as key mediators of human CD8⁺ T cell dysfunction and illuminate novel transcriptional and epigenetic pathways that may be leveraged for therapeutic intervention in cancer and chronic viral infections.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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