Biology subjects

Cimpean, M.

Publications and source records attributed to Cimpean, M..

5 recordsLinked to original sources

bioRxiv2023

IL-15 priming alters IFN-γ regulation in murine NK cells

Natural killer (NK) effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. NK cell production of IFN-{gamma}, an important immunoregulatory cytokine, exhibits activation-specific IFN-{gamma} regulation. Resting murine NK cells exhibit activation-specific metabolic requirements for IFN-{gamma} production, which are reversed for activating receptor-mediated stimulation following IL-15 priming. While both cytokine and activating receptor stimulation leads to similar IFN-{gamma} protein production, only cytokine stimulation upregulates Ifng transcript, suggesting that protein production is translationally regulated after receptor stimulation. Based on these differences in IFN-{gamma} regulation, we hypothesized that ex vivo IL-15 priming of murine NK cells allows a switch to IFN-{gamma} transcription upon activating receptor engagement. Transcriptional analysis of primed NK cells compared to naive cells or cells cultured with low-dose IL-15 demonstrated that primed cells strongly upregulated Ifng transcript following activating receptor stimulation. This was not due to chromatin accessibility changes in the Ifng locus or changes in ITAM signaling, but was associated with a distinct transcriptional signature induced by ITAM stimulation of primed compared to naive NK cells. Transcriptional analyses identified a common signature of c-Myc (Myc) targets associated with Ifng transcription. While Myc marked NK cells capable of Ifng transcription, Myc itself was not required for Ifng transcription using a genetic model of Myc deletion. This work highlights altered regulatory networks in IL-15 primed cells, resulting in distinct gene expression patterns and IFN-{gamma} regulation in response to activating receptor stimulation.

immunology↗

bioRxiv2021

Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease

Recent studies identifying expression quantitative trait loci (eQTL) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells, and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimers disease (AD). We have performed RNA sequencing on four T cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched healthy controls from the Religious Orders Study/Memory and Aging Project. Correlating gene expression data with AD neuropathological traits, and with single nucleotide polymorphisms (SNPs) to detect eQTLs, we identified several significant genes involved in T cell senescence and cytotoxicity, consistent with T cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Overall, our data sheds more light on the genetic basis behind phenotypic changes in T cells during aging and AD.

immunology↗

bioRxiv2019

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Complexity of cell-type composition has created much skepticism surrounding the interpretation of brain bulk-tissue transcriptomic studies. We generated paired tissue genome-wide gene expression data and immunohistochemistry data, enabling us to assess statistical methods for modeling and estimating cellular heterogeneity in the brain. We demonstrate that several algorithms that rely on single-cell and cell-sorted data to define cell marker gene sets yield accurate relative and absolute estimates of constituent cell-type proportions.

neuroscience↗

bioRxiv2018

A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimers disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

neuroscience↗

bioRxiv2017

The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

AbstractWe assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.\n\nOne Sentence SummaryWe report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.

genetics↗