Distinct microbial and immune niches of the human colon

James, Kylie R.; Gomes, Tomás; Elmentaite, Rasa; Kumar, Nitin; Gulliver, Emily; King, Hamish W; Stares, Mark; Bareham, Bethany; Ferdinand, John R.; Petrova, Velislava; Polański, Krzysztof; Forster, Samuel C.; Jarvis, Lorna B.; Suchánek, Ondřej; Howlett, Sarah; James, Louisa K.; Jones, Joanne L.; Meyer, Kerstin B.; Clatworthy, Menna R.; Saeb‐Parsy, Kourosh; Lawley, Trevor D.; Teichmann, Sarah A.

doi:10.1038/s41590-020-0602-z

Cited by 194 publications

(191 citation statements)

References 58 publications

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“…Crucially, all annotated B cell states were observed at reproducible frequencies across patients, regardless of their history of tonsillitis (Figure 2O), although exactly how some of these transcriptional states relate to other human B cell populations will require further work. We also note that we have identified a greater diversity of B cell fates in our paediatric tonsil samples (typically <10 years old) than previous single-cell studies of other human lymphoid tissues from adult donors (typically >40 years old) (Madissoon et al, 2019, James et al, 2020), highlighting the importance of profiling immunologically active tissues to understand B cell maturation. Together, our uniquely comprehensive transcriptomic and repertoire analyses of a model secondary lymphoid organ have allowed us to create a detailed overview of human B cell maturation that will allow us to interrogate gene expression and antibody repertoire dynamics before, during and after maturation in the GC.…”

Section: Resultsmentioning

confidence: 66%

“…Given their relative availability, human tonsils are a useful tissue with which to examine the GC response. It will be of interest for future studies to compare class-specific gene expression differences in other tissues and contexts to determine the contribution of the local cellular environment on B cell maturation (James et al, 2020, Smillie et al, 2019). Similarly, recent technical advances allowing the simultaneous readout of antigen specificity, antibody sequences and gene expression (Setliff et al, 2019) make it possible to examine how different types of antigens may be linked with different B cell phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Single-cell VDJ analysis was performed broadly as described previously (James et al, 2020). Briefly, the number of quality filtered and annotated IgH, IgK or IgL were determined per unique cell barcode prior to integration with single-cell gene expression objects.…”

Section: Methodsmentioning

confidence: 99%

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Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

King

Orban

Riches

et al. 2020

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15In response to antigen challenge, B cells clonally expand, undergo selection and differentiate to produce 16 mature B cell subsets and high affinity antibodies. However, the interplay between dynamic B cell states 17 and their antibody-based selection is challenging to decipher in primary human tissue. We have applied 18 an integrated analysis of bulk and single-cell antibody repertoires paired with single-cell transcriptomics 19 of human B cells undergoing affinity maturation. We define unique gene expression and antibody 20 repertoires of known and novel B cell states, including a pre-germinal centre state primed to undergo 21 class switch recombination. We dissect antibody class-dependent gene expression of germinal centre 22 and memory B cells to find that class switching prior to germinal centre entry dictates the capacity of B 23 cells to undergo antibody-based selection and differentiate. Together, our analyses provide 24 unprecedented resolution into the gene expression and selection dynamics that shape B cell-mediated 25 immunity. 26 27 121 122 157 sampling of IgH sequences from bulk repertoires to enhance genotype correction, identification of 158

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Section: Resultsmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

King

Orban

Riches

et al. 2020

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“…The colon immune cell composition was imputed from the sigmoid colon bulk RNAseq data by CIBERSORTx (https://cibersortx.stanford.edu/ ) [40] In brief, single cell single cell RNAseq dataset (scRNAseq) associated with sigmoid colon was extracted from colon immune atlas of Gut Cell Atlas project by Seurat [41]. The rst part of the CIBERSORTx work ow computed the signature matrix of immune cell populations in sigmoid colon using sigmoid colon scRNAseq dataset.…”

Section: In Silico Cytometry Methodsmentioning

confidence: 99%

Metagenomic Analysis of the Gut Microbiome in Psoriasis Reveals Three Subgroups with Distinct Host-Microbe Interactions

Chang

Yan

Singh

et al. 2020

Preprint

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Background Psoriasis is a chronic, inflammatory skin disease that impacts 2–3% of the global population. Besides skin manifestations, psoriasis patients have increased susceptibility to a number of comorbidities including psoriatic arthritis, cardiovascular disease, and inflammatory bowel disease. To understand the systemic component of psoriasis pathogenesis, we examined the fecal metagenome, host colonic transcriptome, and host peripheral blood immune profiles of psoriasis patients and healthy controls. Results Our analysis showed increased functional diversity in the gut microbiome of psoriasis patients. In addition, we identified microbial species that preferentially associate with psoriasis patients and which have been previously found to associate with other autoimmune diseases. Intriguingly, our data reveal new insights about psoriasis disease heterogeneity, as we identified three psoriasis subgroups that have distinct microbial and host features. Finally, integrating microbial and host features revealed host-microbe interactions that are specific to psoriasis or particular psoriasis subgroups. Conclusion To our knowledge, this is the first study that provides a comprehensive view of gut microbial function and corresponding host response in psoriasis patients. Our findings provide insight into factors that may affect the development of comorbidities in psoriasis patients and may hold diagnostic potential for early identification of psoriasis patients at risk for these comorbidities.

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“…Using an approach based on Bayesian Gaussian Process Latent Variable Modelling (bGPLVM), we identified a bifurcation point between two trajectories, and revealed a role for T cell extrinsic factors in governing Th1/Tfh fate (9). More recently, we employed scRNA-seq to reveal heterogeneity and tissue adaptation of thymic Tregs and colonic CD4 + T cells during steady-state in mice and humans (13, 14). Here, we examined donor antigen presenting cell (APC)-mediated differentiation of allo-reactive donor CD4 + T cells in acute gut GVHD using droplet-based scRNA-seq and computational modelling.…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics of allo-reactive CD4⁺ T cells over time reveals divergent fates during gut GVHD

Engel

Lee

Williams

et al. 2020

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32Acute gastrointestinal Graft-versus-Host-Disease (GVHD) is a primary determinant of mortality after 33 allogeneic hematopoietic stem-cell transplantation (alloSCT). It is mediated by alloreactive donor CD4 + T 34 cells that differentiate into pathogenic subsets expressing IFNγ, IL-17A or GM-CSF, and is regulated by 35 subsets expressing IL-10 and/or Foxp3. Developmental relationships between T-helper states during priming 36 in mesenteric lymph nodes (mLN) and effector function in the GI tract remain undefined at genome-scale. 37We used scRNA-seq and computational modelling to create an atlas of putative differentiation pathways 38 during GVHD. Computational trajectory inference suggested emergence of pathogenic and regulatory states 39 along a single developmental trajectory in mLN. Importantly, we identified an unexpected second trajectory, 40 categorised by little proliferation or cytokine expression, reduced glycolysis, and high TCF1 expression. 41 TCF1 hi cells upregulated α4β7 prior to gut migration and failed to express cytokines therein. Nevertheless, 42 they demonstrated recall potential and plasticity following secondary transplantation, including cytokine or 43Foxp3 expression, but reduced TCF1. Thus, scRNA-seq revealed divergence of allo-reactive CD4 + T cells 44into quiescent and effector states during gut GVHD, reflecting putative heterogenous priming in vivo. These 45 findings, the first at a single-cell level during GVHD over time, can now be used to interrogate T cell 46 differentiation in patients undergoing alloSCT. 47 25. Karmaus PWF, Chen X, Lim SA, Herrada AA, Nguyen TM, Xu B, et al. Metabolic heterogeneity underlies 608 reciprocal fates of TH17 cell stemness and plasticity. Nature. 2019;565(7737):101-5. 609 26. Pepper M, Pagan AJ, Igyarto BZ, Taylor JJ, and Jenkins MK. Opposing signals from the Bcl6 transcription factor 610 and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011;35(4):583-611 95.

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Distinct microbial and immune niches of the human colon

Cited by 194 publications

References 58 publications

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

Metagenomic Analysis of the Gut Microbiome in Psoriasis Reveals Three Subgroups with Distinct Host-Microbe Interactions

Single-cell transcriptomics of allo-reactive CD4⁺ T cells over time reveals divergent fates during gut GVHD

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Distinct microbial and immune niches of the human colon

Cited by 194 publications

References 58 publications

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

Metagenomic Analysis of the Gut Microbiome in Psoriasis Reveals Three Subgroups with Distinct Host-Microbe Interactions

Single-cell transcriptomics of allo-reactive CD4+ T cells over time reveals divergent fates during gut GVHD

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Single-cell transcriptomics of allo-reactive CD4⁺ T cells over time reveals divergent fates during gut GVHD