Ectopic Tcf1 expression reprograms exhausted CD8+ T cells to acquire stem cell-like features [RNA-seq]
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ABSTRACT: The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the transcriptome of Tex cells.
Project description:The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the chromatin accessibility of Tex cells.
Project description:The goal of this study is to determine the capacity of Tcf1 to reprogram exhausted CD8+ T cells for function restoration. Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1 (termed Tex-stem), and Tex-stem cells depend on Tcf1 for generation and persistence. We show that ectopic Tcf1 expression profoundly affected the transcriptome and chromatin accessibility of Tex cells.
Project description:Regulatory T (Treg) cells are important regulators of the immune system and have versatile functions for the homeostasis and repair of tissues. They express the forkhead box transcription factor Foxp3 as a lineage-defining protein. In mature Treg cells, the Foxp3 core promoter is unmethylated indicating that this area could harbor a transcription factor complex to initiate or repress gene expression, respectively. We used an unbiased method to identify Foxp3-promoter-binding transcription factors (TFs) by inverted chromatin immunoprecipitation (IP) followed by quantitative mass spectrometry. We identified several candidate factors which showed Foxp3-promoter suppressive capacity, one of which was T-cell factor 1 (Tcf1). Using viral overexpression and CRISPR/Cas knockout studies, we identified Tcf1 as a repressor of Foxp3 expression in primary conventional CD4 T cells (Tconv). In Tcf1-deficient animals, increased levels of Foxp3intermediateCD25negative T cells were identified in secondary lymphoid tissues, implicating that Tcf1 protects Foxp3-negative T cells from inadvertent Foxp3 expression.
Project description:While distinct NK-like CD57+ and PD-1+ CD8+ exhausted T cell populations (Tex) were both linked to beneficial immunotherapy response in autoimmune Type 1 Diabetes (T1D) patients, relationships between these cell types are poorly understood. We show that PD-1+ and CD57+ Tex populations in this context were epigenetically similar, but CD57+ Tex cells displayed unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also showed reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex showed unappreciated gene expression heterogeneity and shared clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.
Project description:While distinct NK-like CD57+ and PD-1+ CD8+ exhausted T cell populations (Tex) were both linked to beneficial immunotherapy response in autoimmune Type 1 Diabetes (T1D) patients, relationships between these cell types are poorly understood. We show that PD-1+ and CD57+ Tex populations in this context were epigenetically similar, but CD57+ Tex cells displayed unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also showed reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex showed unappreciated gene expression heterogeneity and shared clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.