Similar Datasets
Project description:CD4+ T helper 17 (Th17) cells encompass a spectrum of cell states including homeostatic cells that maintain physiological functions such as barrier integrity and pathogenic cells that drive autoimmune tissue inflammation. Identifying the regulators that determine these cell states will provide means to control tissue inflammation without compromising the physiological functions of Th17 cells. Here, we identified TCF1 as the key regulator that determines Th17 cell state. IL-23, a cytokine critical for inducing pathogenic Th17 cells, decreased TCF1 expression. Consistent with this observation, conditional deletion of Tcf7/TCF1 in mature myelin-specific T cells conferred pathogenicity to homeostatic Th17 cells independent of IL-23. Conversely, sustained TCF1 expression impaired acquisition of pathogenicity. Integration of transcriptional and chromatin accessibility data showed that TCF1 maintained homeostatic state through a regulatory network involving ETS family transcription factors, EGR1, and FOXO1 and by binding to and interfering with RORt activity. Our findings provide mechanistic insight into how the homeostatic and pathogenic Th17 cell states are determined and into the association of genetic variants in TCF7 with susceptibility to autoimmunity.
2024-11-03 | GSE233907 | GEO
Project description:CD4+ T helper 17 (Th17) cells encompass a spectrum of cell states including homeostatic cells that maintain physiological functions such as barrier integrity and pathogenic cells that drive autoimmune tissue inflammation. Identifying the regulators that determine these cell states will provide means to control tissue inflammation without compromising the physiological functions of Th17 cells. Here, we identified TCF1 as the key regulator that determines Th17 cell state. IL-23, a cytokine critical for inducing pathogenic Th17 cells, decreased TCF1 expression. Consistent with this observation, conditional deletion of Tcf7/TCF1 in mature myelin-specific T cells conferred pathogenicity to homeostatic Th17 cells independent of IL-23. Conversely, sustained TCF1 expression impaired acquisition of pathogenicity. Integration of transcriptional and chromatin accessibility data showed that TCF1 maintained homeostatic state through a regulatory network involving ETS family transcription factors, EGR1, and FOXO1 and by binding to and interfering with RORt activity. Our findings provide mechanistic insight into how the homeostatic and pathogenic Th17 cell states are determined and into the association of genetic variants in TCF7 with susceptibility to autoimmunity.
2024-11-03 | GSE233905 | GEO
Project description:Transcription factor TCF1 binds Rorgt and orchestrates a regulatory network that determines homeostatic Th17 cell state
| PRJNA978551 | ENA
Project description:Transcription factor TCF1 binds Rorgt and orchestrates a regulatory network that determines homeostatic Th17 cell state [RNA-seq]
| PRJNA978554 | ENA
Project description:Transcription factor TCF1 binds Rorgt and orchestrates a regulatory network that determines homeostatic Th17 cell state [ATAC-seq]
| PRJNA978555 | ENA
Project description:Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPβ in CD11c+MHCIIhi DCs, gene expression profiles of splenic C/EBPβ-/- DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c+MHCIIhiCD64+ DC compartment was also increased, suggesting that C/EBPβ deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPβ could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ-/- bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPβ plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis.
| S-EPMC7584915 | biostudies-literature
Project description:How does chronic activity modulation lead to global remodeling of proteins at synapses and synaptic scaling? Here we report that guanylate kinase-associated protein (GKAP; also known as SAPAP), a scaffolding molecule linking NMDA receptor-PSD-95 to Shank-Homer complexes, acts in these processes. Overexcitation removes GKAP from synapses via the ubiquitin-proteasome system, whereas inactivity induces synaptic accumulation of GKAP in rat hippocampal neurons. Bidirectional changes in synaptic GKAP amounts are controlled by specific CaMKII isoforms coupled to different Ca(2+) channels. CaMKII? activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP. In contrast, CaMKII? activation via L-type voltage-dependent calcium channels promotes GKAP recruitment by phosphorylating GKAP Ser340 and Ser384, which uncouples GKAP from myosin Va motor complex. Overexpressing GKAP turnover mutants not only hampers activity-dependent remodeling of PSD-95 and Shank but also blocks bidirectional synaptic scaling. Therefore, activity-dependent turnover of PSD proteins orchestrated by GKAP is critical for homeostatic plasticity.
| S-EPMC3804128 | biostudies-literature
Project description:X-ray crystallography has provided tremendous insight into the different structural states of membrane proteins and, in particular, of ion channels. However, the molecular forces that determine the thermodynamic stability of a particular state are poorly understood. Here we analyze the different X-ray structures of an inwardly rectifying potassium channel (Kir1.1) in relation to functional data we obtained for over 190 mutants in Kir1.1. This mutagenic perturbation analysis uncovered an extensive, state-dependent network of physically interacting residues that stabilizes the pre-open and open states of the channel, but fragments upon channel closure. We demonstrate that this gating network is an important structural determinant of the thermodynamic stability of these different gating states and determines the impact of individual mutations on channel function. These results have important implications for our understanding of not only K+ channel gating but also the more general nature of conformational transitions that occur in other allosteric proteins.
| S-EPMC4087272 | biostudies-literature
Project description:Variability of spiking activity is ubiquitous throughout the brain but little is known about its contextual dependance. Trial-to-trial spike count variability, estimated by the Fano Factor (FF), and within-trial spike time irregularity, quantified by the coefficient of variation (CV), reflect variability on long and short time scales, respectively. We co-analyzed FF and the local coefficient of variation (CV2) in monkey motor cortex comparing two behavioral contexts, movement preparation (wait) and execution (movement). We find that the FF significantly decreases from wait to movement, while the CV2 increases. The more regular firing (expressed by a low CV2) during wait is related to an increased power of local field potential (LFP) beta oscillations and phase locking of spikes to these oscillations. In renewal processes, a widely used model for spiking activity under stationary input conditions, both measures are related as FF ? CV2. This expectation was met during movement, but not during wait where FF ? CV22. Our interpretation is that during movement preparation, ongoing brain processes result in changing network states and thus in high trial-to-trial variability (expressed by a high FF). During movement execution, the network is recruited for performing the stereotyped motor task, resulting in reliable single neuron output. Our interpretation is in the light of recent computational models that generate non-stationary network conditions.
| S-EPMC6052126 | biostudies-literature
Project description:SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a(-/-) mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A(+) ?? and CD4(+) Th17 cells are already expanded in the lungs of serpinb1a(-/-) mice at steady-state. Both ?? and ??(+) CD4(+) CCR6(+) T cells isolated from the lungs of naive serpinb1a(-/-) mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (ROR?t)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in ?? T cells. In addition to the lung, IL-17A(+) ?? and CD4(+) Th17 cells were increased in the spleen of naive serpinb1a(-/-) mice, despite normal ?? and ?? T cell development in the thymus. Within the ?? T cell compartment, loss of serpinb1a prompted selective expansion of V?4(+) and V?6/V?1(+) cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A(+) ?? and CD4(+) Th17 cell subsets vis-à-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype.
| S-EPMC3923080 | biostudies-literature