scholarly journals Steroid receptor coactivator 3 (SRC-3/AIB1) is enriched and functional in mouse and human Tregs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bryan C. Nikolai ◽  
Prashi Jain ◽  
David L. Cardenas ◽  
Brian York ◽  
Qin Feng ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Immune Evasion ◽  
Cell Types ◽  
Phenotypic Characteristics ◽  
Central Tolerance ◽  
Steroid Receptor Coactivator ◽  
And Function ◽  
Cd4 Lymphocytes ◽  
Failure Of Induction

AbstractA subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs.

The paracaspase MALT1 in psoriasis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Stephan Hailfinger ◽  
Klaus Schulze-Osthoff
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factors ◽  
Skin Disease ◽  
Cell Types ◽  
Cytokine Receptors ◽  
Molecular Scaffold ◽  
Therapeutic Implications ◽  
Stimulation Of

Abstract Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

scholarly journals Age-Related Changes in Thymic Central Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Jayashree Srinivasan ◽  
Jessica N. Lancaster ◽  
Nandini Singarapu ◽  
Laura P. Hale ◽  
Lauren I. R. Ehrlich ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Adult Transition ◽  
Treg Function ◽  
Age Related ◽  
And Function ◽  
Antigen Presenting ◽  
Age Related Changes

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.

Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2421-2427 ◽  
Author(s):  
Laura Piccio ◽  
William Vermi ◽  
Kent S. Boles ◽  
Anja Fuchs ◽  
Carey A. Strader ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Orphan Receptor ◽  
T Cell Proliferation ◽  
Central Nervous Systems ◽  
And Function ◽  
Antigen Presenting

AbstractSignal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPα binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPβ1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPβ2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPβ2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPα, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPβ2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

scholarly journals Immunomodulation by Gut Microbiota: Role of Toll-Like Receptor Expressed by T Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Mariagrazia Valentini ◽  
Alessia Piermattei ◽  
Gabriele Di Sante ◽  
Giuseppe Migliara ◽  
Giovanni Delogu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Gut Microbiota ◽  
Cell Types ◽  
Mutual Regulation ◽  
Close Relationship ◽  
Numerous Cell ◽  
Specific Receptors ◽  
And Function

A close relationship exists between gut microbiota and immune responses. An imbalance of this relationship can determine local and systemic immune diseases. In fact the immune system plays an essential role in maintaining the homeostasis with the microbiota that normally resides in the gut, while, at the same time, the gut microbiota influences the immune system, modulating number and function of effector and regulatory T cells. To achieve this aim, mutual regulation between immune system and microbiota is achieved through several mechanisms, including the engagement of toll-like receptors (TLRs), pathogen-specific receptors expressed on numerous cell types. TLRs are able to recognize ligands from commensal or pathogen microbiota to maintain the tolerance or trigger the immune response. In this review, we summarize the latest evidences about the role of TLRs expressed in adaptive T cells, to understand how the immune system promotes intestinal homeostasis, fights invasion by pathogens, and is modulated by the intestinal microbiota.

HIV‐1 Nef equips dendritic cells to reduce survival and function of CD8 + T cells: a mechanism of immune evasion

2004 ◽  
Vol 18 (12) ◽  
pp. 1459-1461 ◽  
Author(s):  
Maria Giovanna Quaranta ◽  
Benedetta Mattioli ◽  
Luciana Giordani ◽  
Marina Viora
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Evasion ◽  
Cd8 T Cells ◽  
And Function ◽  
Hiv 1

scholarly journals Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors

2020 ◽  
Author(s):  
Shiri Kult ◽  
Tsviya Olender ◽  
Marco Osterwalder ◽  
Sharon Krief ◽  
Ronnie Blecher-Gonen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Single Molecule ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Regulatory Elements ◽  
Transcriptional Enhancer ◽  
Molecular Identity ◽  
And Function

AbstractThe connection between different tissues is vital for the development and function of any organs and systems. In the musculoskeletal system, the attachment of elastic tendons to stiff bones poses a mechanical challenge that is solved by the formation of a transitional tissue, which allows the transfer of muscle forces to the skeleton without tearing. Here, we show that tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, which is regulated by sharing regulatory elements with these cells and by Krüppel-like factors transcription factors (KLF).To uncover the molecular identity of attachment cells, we first applied high-throughput RNA sequencing to murine humeral attachment cells. The results, which were validated by in situ hybridization and single-molecule in situ hybridization, reveal that attachment cells express hundreds of chondrogenic and tenogenic genes. In search for the underlying mechanism allowing these cells to express these genes, we performed ATAC sequencing and found that attachment cells share a significant fraction of accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis further revealed transcriptional enhancer signatures for the majority of these regions. We then examined a subset of these regions using transgenic mouse enhancer reporter. Results verified the shared activity of some of these enhancers, supporting the possibility that the transcriptome of attachment cells is regulated by enhancers with shared activities in tenocytes or chondrocytes. Finally, integrative chromatin and motif analyses, as well as the transcriptome data, indicated that KLFs are regulators of attachment cells. Indeed, blocking the expression of Klf2 and Klf4 in the developing limb mesenchyme led to abnormal differentiation of attachment cells, establishing these factors as key regulators of the fate of these cells.In summary, our findings show how the molecular identity of bi-fated attachment cells enables the formation of the unique transitional tissue that connect tendon to bone. More broadly, we show how mixing the transcriptomes of two cell types through shared enhancers and a dedicated set of transcription factors can lead to the formation of a new cell fate that connects them.

scholarly journals Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Sheng Tu ◽  
Xu Lin ◽  
Jili Qiu ◽  
Jiaqi Zhou ◽  
Hui Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Malignant Disease ◽  
Immune Therapy ◽  
Cell Types ◽  
Different Types ◽  
The Central Nervous System ◽  
And Function ◽  
The Relationship

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.

Transcriptional Control of Lung Morphogenesis

2007 ◽  
Vol 87 (1) ◽  
pp. 219-244 ◽  
Author(s):  
Yutaka Maeda ◽  
Vrushank Davé ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transcription Factors ◽  
Transcriptional Control ◽  
Family Members ◽  
Cell Types ◽  
Branching Morphogenesis ◽  
Early Embryo ◽  
Normal Lung ◽  
Thyroid Transcription Factor 1 ◽  
Lung Morphogenesis ◽  
And Function

The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), β-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.

Characterization of Nur77+ Cells in Murine Peripheral Blood.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1361-1361
Author(s):  
Harper Hubbeling ◽  
Thomas Beck ◽  
Amy Moran ◽  
Kristin Hogquist ◽  
Jonathan Maltzman ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Orphan Nuclear Receptor ◽  
Phenotypic Differences ◽  
Additional Information ◽  
Nuclear Receptor Family ◽  
And Function ◽  
External Stimuli

Abstract Abstract 1361 Poster Board I-385 The expression of Nur77/NR4A1, one member of the Nur Orphan Nuclear Receptor family, is tightly regulated in many cell types, including myeloid and lymphoid lineages, and can change rapidly in response to a variety of external stimuli. Best known for its role in regulating apoptosis by either transcribing lethal genes or by initiating mitochondrial production of cytochrome c, Nur77 may also play other non-apoptotic roles. In an effort to understand the fate and function of cells that upregulate Nur77, we developed a transgenic Nur77-eGFP reporter mouse. Our analysis of cells in the peripheral blood of these mice reveals two populations of circulating cells that express GFP (Nur77) ‘constitutively’: T lymphocytes and a subset of monocytes. Our preliminary data suggest that the GFP+ T cells, which, interestingly are enriched for regulatory T cells, are recent thymic emigrants that have upregulated Nur77 as a consequence of TCR stimulation during maturation. Our observations also indicate that the GFP+ monocytes define a subpopulation of ‘patrolling’ cells that may ultimately differentiate into splenic dendritic cells. Understanding the identity of these circulating GFP+ cells should provide us with insights into the regulation and function of Nur77 itself. The analysis may also clarify the significance of phenotypic differences among blood cell subtypes by providing additional information about cell origin and activity. We thank the Arnold and Mabel Beckman Foundation (HH), HHMI (TB), and NSF (#MCB-0744570 (JP and NC)) for their support for this work. Disclosures No relevant conflicts of interest to declare.

scholarly journals Identification and functional characterization of circular RNAs in pericytes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Glaser ◽  
A.W Heumueller ◽  
M Klangwart ◽  
A Wiederer ◽  
D John ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Cell Biology ◽  
Functional Characterization ◽  
Cell Types ◽  
Circular Rna ◽  
Circular Rnas ◽  
Funding Source ◽  
Factor Screening ◽  
And Function

Abstract Background Circular RNAs (circRNAs) are generated by back-splicing. They are known to be robustly expressed in a variety of mammalian cell types and organism and have been reported to influence cell biology by acting e.g. as microRNA sponges or regulating host gene expression. Recently, our group reported functionally relevant circRNA expression in endothelial cells. Despite their important role in the cardiovascular system, the expression and function of circRNAs in pericytes is not well studied. Pericytes are perivascular mural cells, important for vessel maturation and endothelial barrier function. Their recruitment towards endothelial cells is mainly meditated by platelet-derived growth factor (PDGF) signaling. However, a more precise understanding of the regulation of pericyte differentiation and survival is necessary. Objective Here, we analyse circRNA expression in pericytes and demonstrate biological relevance of the hypoxia regulated circular RNA PLOD2 (cPLOD2). Methods and results Using RNA Sequencing in ribosomal depleted RNA we characterized the expression of circRNAs in human pericytes under normoxic and hypoxic (1% O2, 48h) conditions. We identified several circular RNAs being regulated upon hypoxia. The identified circular RNAs demonstrated resistance towards RNase-R digestion and lacking of poly-adenylation. Some of them were found to be localized and in the cytosol, whereas others also occur in the nucleus of the cells. Especially cPLOD2 raised our attention since it is significantly upregulated and robustly expressed upon hypoxia. Silencing cPLOD2 by siRNA resulted in significant de-differentiation of pericytes that went along with a loss of cell viability. Mechanistically, transcription factor screening assays revealed that silencing of cPLOD2 enhances the activity of the transcription factors ELK1/SRF, which have been documented to result in de-differentiation of smooth muscle cells. Conclusion Here we characterize the expression pattern of circRNAs in human primary pericytes. Among others, cPLOD2 significantly regulates pericyte function. Our results indicate hypoxia as a major regulator of circRNA expression in pericytes and show that circRNAs are capable of regulating pericyte function by modulating activity of transcription factors. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Forschungsgesellschaft (DFG) - SFB834; Deutsche Gesellschaft für Herz-Kreislaufforschung (DZHK)

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