2026-09-19T00:57:10Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/1645002026-01-13T03:36:48Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Walker, Bruce D.
Traunbauer, Anna Katharina
Massachusetts Institute of Technology. Department of Biology
2026-01-12T19:40:40Z
2026-01-12T19:40:40Z
2025-09
2025-11-10T19:58:47.230Z
https://hdl.handle.net/1721.1/164500
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.
Ph.D.
Massachusetts Institute of Technology
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https://rightsstatements.org/page/InC-EDU/1.0/
The novel roles of BCL6 and BATF3 in regulating human
CD8⁺ T cell dysfunction
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Doctor of Philosophy
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<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.</Abstract>
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