Allergic airway recall responses require IL-9 from resident memory CD4 + T cells DOI
Benjamin J. Ulrich, Rakshin Kharwadkar,

Michelle Chu

et al.

Science Immunology, Journal Year: 2022, Volume and Issue: 7(69)

Published: March 18, 2022

Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term cells that mediate allergic recall responses not well defined. In this report, using mouse model allergen exposure followed by an allergen-free rest period, we characterized subpopulation CD4+ secreted IL-9 as obligate effector cytokine. IL-9-secreting had resident cell phenotype, and blocking during challenge or deleting from significantly diminished airway inflammation hyperreactivity. in recall-specific manner, secretion was amplified IL-33. Using scRNA-seq scATAC-seq, defined cellular distinct population proallergic cytokine pattern. Thus, inflammation, multicytokine-producing required for response.

Language: Английский

Confronting false discoveries in single-cell differential expression DOI Creative Commons
Jordan W. Squair, Matthieu Gautier, Claudia Kathe

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Sept. 28, 2021

Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available identify differentially expressed genes, principles that distinguish these and their performance remain unclear. Here, we show relative is contingent on ability account for variation between biological replicates. Methods ignore this inevitable biased prone false discoveries. Indeed, most widely used can discover hundreds genes absence differences. To exemplify principles, exposed true discoveries injured mouse spinal cord.

Language: Английский

Citations

623
Bifidobacteria-mediated immune system imprinting early in life DOI Creative Commons
Bethany M. Henrick, Lucie Rodriguez, Tadepally Lakshmikanth

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(15), P. 3884 - 3898.e11

Published: June 17, 2021

Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients to specialized microbes that turn benefit host's immune system. Such bacteria have co-evolved with humans but are now increasingly rare modern societies. Here we show a lack bifidobacteria, particular depletion genes required for human milk oligosaccharide (HMO) utilization from metagenome, is associated systemic inflammation dysregulation life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) Th17 cytokines were silenced interferon β (IFNβ) was induced. Fecal water EVC001-supplemented contains abundant indolelactate B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 Th2 cells during polarization, functional link between beneficial immunoregulation first months

Language: Английский

Citations

527
Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease DOI
Seyhan Yazar, José Alquicira-Hernández, Kristof Wing

et al.

Science, Journal Year: 2022, Volume and Issue: 376(6589)

Published: April 7, 2022

The human immune system displays substantial variation between individuals, leading to differences in susceptibility autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells 982 healthy subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing type-specific effects on gene expression. subsequently show how eQTLs have dynamic allelic B that are transitioning naïve memory states demonstrate commonly segregating alleles lead interindividual function. Finally, using a Mendelian randomization approach, identify the causal route by which 305 risk contribute disease at cellular level. This work brings together genetic epidemiology scRNA-seq uncover drivers of system.

Language: Английский

Citations

345
The immunology of multiple sclerosis DOI
Kathrine E. Attfield, Lise Torp Jensen, Max Kaufmann

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(12), P. 734 - 750

Published: May 4, 2022

Language: Английский

Citations

228
Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs DOI Creative Commons
Shuai He,

Lin-he Wang,

Yang Liu

et al.

Genome biology, Journal Year: 2020, Volume and Issue: 21(1)

Published: Dec. 1, 2020

Abstract Background As core units of organ tissues, cells various types play their harmonious rhythms to maintain the homeostasis human body. It is essential identify characteristics in organs and regulatory networks for understanding biological mechanisms related health disease. However, a systematic comprehensive single-cell transcriptional profile across multiple normal adult missing. Results We perform transcriptomes 84,363 derived from 15 tissue one donor generate an cell atlas. The atlas depicts 252 subtypes cells, including major such as T, B, myeloid, epithelial, stromal well novel COCH + fibroblasts FibSmo each which distinguished by marker genes profiles. These collectively contribute heterogeneity organs. Moreover, T B receptor repertoire comparisons trajectory analyses reveal direct clonal sharing with developmental states among different tissues. Furthermore, markers, transcription factors, ligand-receptor pairs are identified potential functional regulations maintaining Conclusions reveals inter- intra-organ provides useful resource uncovering key events during development diseases context

Language: Английский

Citations

179
Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes DOI

Evgeny Kiner,

Elijah Willie,

Brinda Vijaykumar

et al.

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(2), P. 216 - 228

Published: Jan. 18, 2021

Language: Английский

Citations

153
Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data DOI
Martin Jinye Zhang, Kangcheng Hou, Kushal K. Dey

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(10), P. 1572 - 1580

Published: Sept. 1, 2022

Language: Английский

Citations

133
Engineering cytokine therapeutics DOI Open Access
Jeroen Deckers, Tom Anbergen, Ayla M. Hokke

et al.

Nature Reviews Bioengineering, Journal Year: 2023, Volume and Issue: 1(4), P. 286 - 303

Published: Feb. 16, 2023

Language: Английский

Citations

122
Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation DOI Creative Commons
Blagoje Soskic,

Eddie Cano-Gamez,

Deborah J. Smyth

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(6), P. 817 - 826

Published: May 26, 2022

Abstract During activation, T cells undergo extensive gene expression changes that shape the properties of to exert their effector function. Understanding regulation this process could help explain how genetic variants predispose immune diseases. Here, we mapped effects on (expression quantitative trait loci (eQTLs)) using single-cell transcriptomics. We profiled 655,349 CD4 + cells, capturing transcriptional states unstimulated and three time points cell activation in 119 healthy individuals. This identified 38 clusters, including transient clusters were only present at individual activation. found 6,407 genes whose was correlated with variation, which 2,265 (35%) dynamically regulated during Furthermore, 127 by associated immune-mediated diseases, significant enrichment for dynamic effects. Our results emphasize importance studying context-specific provide insights into mechanisms underlying susceptibility

Language: Английский

Citations

111
A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers DOI
Marine Fidelle, Conrad Rauber, Carolina Alves Costa Silva

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6649)

Published: June 8, 2023

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but mechanisms underlying their immunosuppressive effects remain unknown. By inducing down-regulation mucosal addressin adhesion molecule (MAdCAM-1) ileum, post-ABX gut recolonization by Enterocloster species drove emigration enterotropic α4β7+CD4+ regulatory T 17 cells into tumor. These deleterious ABX were mimicked oral gavage species, genetic deficiency, or antibody-mediated neutralization MAdCAM-1 and its receptor, α4β7 integrin. contrast, fecal microbiota transplantation interleukin-17A prevented ABX-induced immunosuppression. In independent lung, kidney, bladder patient cohorts, low serum levels soluble had a negative prognostic impact. Thus, MAdCAM-1-α4β7 axis constitutes an actionable immune checkpoint immunosurveillance.

Language: Английский

Citations

103