scholarly journals Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection pre-T cells

2021 ◽  
Author(s):  
Jeremy J Ratiu ◽  
Qun Wang ◽  
Naren Mehta ◽  
Melissa J Harnois ◽  
Devon DiPalma ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Development ◽  
Cell Compartment ◽  
Dependent Cell ◽  
Selection For ◽  
Sting Pathway ◽  
And Control

AbstractProduction of a diverse peripheral T cell compartment requires massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment at the DN2 stage and following successful rearrangement and selection for functional TCRβ chains in DN3 thymocytes, which promotes development of DN4 cells to the DP stage. Signals driving expansion of DN2 thymocytes are well studied, however, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-β-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor controlling the survival of proliferating post-β-selection thymocytes and demonstrates a key role for the cGAS/STING pathway driving apoptosis of developing T cells.

Separate Ways

2007 ◽  
Vol 2007 (369) ◽  
pp. tw23-tw23
Author(s):  
Stephen Simpson
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Anatomical Location ◽  
Γδ T Cell ◽  
Link Type ◽  
Common Precursor

Two dominant lineages of T cells (αβ and γδ T cells) are highly distinct in function and anatomical location yet share a common precursor within the thymus. Exactly how one cell fate is decided over another remains unresolved. Melichar et al. present evidence that selection to the γδ T cell branch in the thymus is controlled by the transcription factor SOX13, which supports and possibly even initiates γδ T cell development while opposing differentiation of their αβ T cell brethren. The authors noted that SOX13 inhibited an important effector of the central T cell developmental signaling pathway mediated by the Wnt protein. H. J. Melichar, K. Narayan, S. D. Der, Y. Hiraoka, N. Gardiol, G. Jeannet, W. Held, C. A. Chambers, J. Kang, Regulation of γδ versus αβ T lymphocyte differentiation by the transcription factor SOX13. Science315, 230-233 (2007). [Abstract][Full Text]

Regulation of γδ Versus αß T Lymphocyte Differentiation by the Transcription Factor SOX13

Science ◽  
2007 ◽  
Vol 315 (5809) ◽  
pp. 230-233 ◽  
Author(s):  
Heather J. Melichar ◽  
Kavitha Narayan ◽  
Sandy D. Der ◽  
Yoshiki Hiraoka ◽  
Noemie Gardiol ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Molecular Mechanisms ◽  
T Cell Development ◽  
Γδ T Cells ◽  
T Cell Differentiation ◽  
Specific Gene ◽  
T Cell Factor ◽  
Fate Decision

αβ and γδ T cells originate from a common, multipotential precursor population in the thymus, but the molecular mechanisms regulating this lineage-fate decision are unknown. We have identified Sox13 as a γδ-specific gene in the immune system. Using Sox13 transgenic mice, we showed that this transcription factor promotes γδ T cell development while opposing αβ T cell differentiation. Conversely, mice deficient in Sox13 expression exhibited impaired development of γδ T cells but not αβ T cells. One mechanism of SOX13 function is the inhibition of signaling by the developmentally important Wnt/T cell factor (TCF) pathway. Our data thus reveal a dominant pathway regulating the developmental fate of these two lineages of T lymphocytes.

scholarly journals Expression of the CD4 gene requires a Myb transcription factor.

1992 ◽  
Vol 12 (4) ◽  
pp. 1592-1604 ◽  
Author(s):  
G Siu ◽  
A L Wurster ◽  
J S Lipsick ◽  
S M Hedrick
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Tissue Specificity ◽  
T Cell Development ◽  
Developmental Expression ◽  
Myb Transcription Factor ◽  
Differentiation Antigen ◽  
Developmentally Regulated ◽  
Recognition Molecule

We have analyzed the control of developmental expression of the CD4 gene, which encodes an important recognition molecule and differentiation antigen on T cells. We have determined that the CD4 promoter alone functions at high levels in the CD4+ CD8- mature T cell but not at the early CD4+ CD8+ stage of T-cell development. In addition, the CD4 promoter functions only in T lymphocytes; thus, the stage and tissue specificity of the CD4 gene is mediated in part by its promoter. We have determined that a Myb transcription factor binds to the CD4 promoter and is critical for full promoter function. Thus, Myb plays an important role in the expression of T-cell-specific developmentally regulated genes.

scholarly journals Functional definition of a transcription factor hierarchy regulating T cell lineage commitment

2020 ◽  
Vol 6 (31) ◽  
pp. eaaw7313 ◽  
Author(s):  
Laura Garcia-Perez ◽  
Farbod Famili ◽  
Martijn Cordes ◽  
Martijn Brugman ◽  
Marja van Eggermond ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Notch Signaling ◽  
Target Genes ◽  
T Cell Development ◽  
Cell Lineage ◽  
Specific Protein ◽  
Cell Development

T cell factor 1 (Tcf1) is the first T cell–specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell–committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.

scholarly journals A Role for Bcl-2 in Notch1-Dependent Transcription in Thymic Lymphoma Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Ronit Vogt Sionov ◽  
Shlomit Kfir-Erenfeld ◽  
Rachel Spokoini ◽  
Eitan Yefenof
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Double Negative ◽  
Double Positive ◽  
Lymphoma Cells ◽  
Thymic Lymphoma ◽  
Induced Apoptosis

Notch1 is a transcription factor important for T-cell development. Notch1 is active in double negative (DN) thymocytes, while being depressed in double positive (DP) thymocytes. Synchronously, the expression of Bcl-2 becomes downregulated during the transition from DN to DP thymocytes. We previously observed that overexpression of an intracellular active Notch1 (ICN) in Bcl-2-positive 2B4 T cells leads to the transcription of Notch1-regulated genes. However, these genes were not induced in Bcl-2-negative DP PD1.6 thymic lymphoma cells overexpressing ICN. Here we show that, when Bcl-2 is simultaneously introduced into these cells, Notch-regulated genes are transcribed. Only in the presence of both Bcl-2 and ICN, PD1.6 thymic lymphoma cells become resistant to glucocorticoid (GC)-induced apoptosis. Our data suggest that Bcl-2 plays a role in modulating Notch1 function in T cells.

Expression of the CD4 gene requires a Myb transcription factor

1992 ◽  
Vol 12 (4) ◽  
pp. 1592-1604
Author(s):  
G Siu ◽  
A L Wurster ◽  
J S Lipsick ◽  
S M Hedrick
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Tissue Specificity ◽  
T Cell Development ◽  
Developmental Expression ◽  
Myb Transcription Factor ◽  
Differentiation Antigen ◽  
Developmentally Regulated ◽  
Recognition Molecule

We have analyzed the control of developmental expression of the CD4 gene, which encodes an important recognition molecule and differentiation antigen on T cells. We have determined that the CD4 promoter alone functions at high levels in the CD4+ CD8- mature T cell but not at the early CD4+ CD8+ stage of T-cell development. In addition, the CD4 promoter functions only in T lymphocytes; thus, the stage and tissue specificity of the CD4 gene is mediated in part by its promoter. We have determined that a Myb transcription factor binds to the CD4 promoter and is critical for full promoter function. Thus, Myb plays an important role in the expression of T-cell-specific developmentally regulated genes.

scholarly journals Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5376-5384 ◽  
Author(s):  
Yair Benita ◽  
Zhifang Cao ◽  
Cosmas Giallourakis ◽  
Chun Li ◽  
Agnès Gardet ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Development ◽  
Gene Enrichment ◽  
Cell Tissue ◽  
Development And Differentiation ◽  
A Cell ◽  
And Function

Abstract The identification of transcriptional regulatory networks, which control tissue-specific development and function, is of central importance to the understanding of lymphocyte biology. To decipher transcriptional networks in T-cell development and differentiation we developed a browsable expression atlas and applied a novel quantitative method to define gene sets most specific to each of the represented cell subsets and tissues. Using this system, body atlas size datasets can be used to examine gene enrichment profiles from a cell/tissue perspective rather than gene perspective, thereby identifying highly enriched genes within a cell type, which are often key to cellular differentiation and function. A systems analysis of transcriptional regulators within T cells during different phases of development and differentiation resulted in the identification of known key regulators and uncharacterized coexpressed regulators. ZBTB25, a BTB-POZ family transcription factor, was identified as a highly T cell–enriched transcription factor. We provide evidence that ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. Together, these findings suggest a novel mechanism for NF-AT mediated gene expression and the compendium of expression data provides a quantitative platform to drive exploration of gene expression across a wide range of cell/tissue types.

scholarly journals Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 155
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
Vamsi Kota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
High Risk ◽  
Lung Adenocarcinoma ◽  
Risk Group ◽  
High Risk Group ◽  
Free Survival ◽  
Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

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