{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/164500"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/164500","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"The novel roles of BCL6 and BATF3 in regulating human CD8⁺ T cell dysfunction","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_html":"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_has_math":false,"creators":["Traunbauer, Anna Katharina"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Biology","school":null,"contributors":[],"advisors":["Walker, Bruce D."],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-09","date_published":"2025-09","updated_at":"2026-07-22T22:21:19Z","subjects":[],"languages":[],"rights":["In Copyright - Educational Use Permitted","Copyright retained by author(s)"],"rights_urls":["https://rightsstatements.org/page/InC-EDU/1.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1721.1/164500","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Walker, Bruce D."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["The novel roles of BCL6 and BATF3 in regulating human CD8⁺ T cell dysfunction"]}]}],"canonical_facts":{"dc:contributor.advisor":["Walker, Bruce D."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Biology"],"dc:creator":["Traunbauer, Anna Katharina"],"dc:date.accessioned":["2026-01-12T19:40:40Z"],"dc:date.available":["2026-01-12T19:40:40Z"],"dc:date.issued":["2025-09"],"dc:description.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."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["https://hdl.handle.net/1721.1/164500"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["In Copyright - Educational Use Permitted","Copyright retained by author(s)"],"dc:rights.uri":["https://rightsstatements.org/page/InC-EDU/1.0/"],"dc:title":["The novel roles of BCL6 and BATF3 in regulating human CD8⁺ T cell dysfunction"],"dc:type":["Thesis"],"thesis:degree_name":["Doctoral","Doctor of Philosophy"]},"updated_at":"2026-07-22T22:21:19Z"}