PMCID
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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T cell populations showed distinct cytokine and chemokine expression patterns (Extended Data Fig. 3c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The CD-associated TFH-like population, showed high CXCL13 and IL21 expression, with IFNG and IL21 coexpression (Fig. 3j,k), similarly to gluten-specific T cells.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TFH-like cells expressed TNFSF8, CCL1, CCL22 and CXCL10, as well as IL17F (Extended Data Fig. 3c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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IL17F expression was not seen in the IL17ARORCIL23RCCR6 TH17 population, nor did the TH17 cluster show TRBV7-2 enrichment (Extended Data Fig. 3b,d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Oral gluten challenge in CD drives rapid circulating cytokine responses, including IL-2, CXCL8, CXCL10 and IL-6 (ref. ).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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CXCL8 expression was highest in CCR7 TFH CD4 T cells, CXCL10 was detected in TFH-like CD4 T cells, while IL6 was detected in Treg cells (Extended Data Fig. 3c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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IL2 expression was low within the CD4 compartment, as expected without gluten challenge.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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We examined transcription factor (TF), and regulon expression within CD4 subsets, with canonical TFs and regulons of TH17 and Treg cell function expressed as expected (Extended Data Fig. 3e–g).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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IKZF1 and its regulon were upregulated in TFH-like cells, with intermediate expression of RUNX1, BATF and IRF3.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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We examined B cell lineages in dataset 2 (pediatric; Extended Data Fig. 4a,b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Both IgA and IgM plasma cells were increased in CD (Extended Data Fig. 4c–f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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A population of CXCR5 B cells (MS4A1CD19CD20) were present, with a shift toward the CD27 memory B cell phenotype in CD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Gene signatures of age-related B cells (an inflammation-associated population in autoimmune disease), including ITGAM, ITGAX, CD86 and BATF, were expressed most highly in CD27 B cell populations, while a key age-related B cell TF, TBX21, was highly expressed in cycling B cells (Extended Data Fig. 4b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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HLA class II gene and protein expression, specifically HLA-DQ, was highest in CD27 and cycling B cells (Extended Data Fig. 4g,h).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Intestinal myeloid cell populations are impacted by CD and may be involved in antigen presentation and oral tolerance.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Myeloid cells (dataset 2) formed 11 transcriptionally distinct clusters, including macrophages, conventional dendritic cells and plasmacytoid dendritic cells (Supplementary Fig. 2a–c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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HLA-DQ expression was highest on macrophage populations, particularly CD163 cells.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In contrast to prior studies, CD163 macrophages were reduced in ACD, with expansion of a conventional dendritic cell 2 population, which showed increased IL-1B expression (Supplementary Fig. 2d,e).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Intestinal CD8 T cells showed considerable heterogeneity in transcriptional states, with multiple tissue-resident memory CD8 T (TRM) cells, including an ITGAEIL7R population, a CCL4CD69ITGAE population and two subsets of ITGAE TRM cells (Fig. 4, Extended Data Fig. 5a and Supplementary Table 7).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These aligned with gene signatures defining subsets of bona fide human TRM cells.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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FGFBP2 effectors aligned with previously described ITGB2ITGAE TRM cells, while TRM(1), TRM(2) and cycling subsets aligned with CD103 TRM cells (Extended Data Fig. 5b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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CCL4 and IL7R populations likely represent intermediate states in TRM cell development.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Small natural IEL and cycling MKI67 populations were seen (Extended Data Fig. 5b,c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Analogous CD8 T cell subsets were seen in dataset 2 (Fig. 4d,e and Extended Data Fig. 5a), with additional resolution for tissue-resident γδ T cells, and innate-like T cells (mucosal-associated invariant T cells and Vδ2Vγ9 cells).Fig.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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4CD8 T cells in CD.a–c, Dataset 1 intestinal CD8 T cells in health and CD (adult—10x Genomics).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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a, UMAP plot of intestinal CD8 T cells in health and CD (n = 8).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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b, Bubble plot showing the expression of selected genes defining specific cluster identities.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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c, UMAP plots overlaid with expression of IL7R, GZMK, ITGAE, CXCR6, GZMA, LAYN, ENTPD1, TNFRSF9, TIGIT and HLA-DRB1.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Dataset 2 intestinal CD8 T cells in health and CD (pediatric—BD Rhapsody; d–f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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d, UMAP plot of intestinal CD8 T cells in health and CD (n = 15).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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e, Bubble plot showing the expression of selected genes and proteins defining specific cluster identities.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Gene/protein expression indicated by color; proportion of cells expressing the gene/protein indicated by bubble size.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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f, Local neighborhood enrichment of CD8 cells in ACD versus HCs (dataset 1).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Color indicates enrichment (log fold change) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates −log10FDR.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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g, Scatterplot of mean proportion (± s.e.)
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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of CD8 T cell clusters in HCs (n = 3) versus ACD (n = 5).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Clusters above the line of unity are enriched in ACD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h,i, TRM(2) (h) and cycling (i) CD8 T cell phenotype populations in HCs and CD, as a proportion of total CD8 T cells in dataset 1 (HCs n = 3, ACD n = 5) and dataset 2 (HCs n = 5, ACD n = 10).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h,i, Two-sided Mann–Whitney test.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Data are presented as the mean values ± s.e.m.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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nIEL, natural intraepithelial lymphocyte.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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a–c, Dataset 1 intestinal CD8 T cells in health and CD (adult—10x Genomics).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
a, UMAP plot of intestinal CD8 T cells in health and CD (n = 8).
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
b, Bubble plot showing the expression of selected genes defining specific cluster identities.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
c, UMAP plots overlaid with expression of IL7R, GZMK, ITGAE, CXCR6, GZMA, LAYN, ENTPD1, TNFRSF9, TIGIT and HLA-DRB1.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Dataset 2 intestinal CD8 T cells in health and CD (pediatric—BD Rhapsody; d–f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
d, UMAP plot of intestinal CD8 T cells in health and CD (n = 15).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
e, Bubble plot showing the expression of selected genes and proteins defining specific cluster identities.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Gene/protein expression indicated by color; proportion of cells expressing the gene/protein indicated by bubble size.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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f, Local neighborhood enrichment of CD8 cells in ACD versus HCs (dataset 1).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Color indicates enrichment (log fold change) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates −log10FDR.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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g, Scatterplot of mean proportion (± s.e.)
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
of CD8 T cell clusters in HCs (n = 3) versus ACD (n = 5).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Clusters above the line of unity are enriched in ACD.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
h,i, TRM(2) (h) and cycling (i) CD8 T cell phenotype populations in HCs and CD, as a proportion of total CD8 T cells in dataset 1 (HCs n = 3, ACD n = 5) and dataset 2 (HCs n = 5, ACD n = 10).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
h,i, Two-sided Mann–Whitney test.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Data are presented as the mean values ± s.e.m.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
nIEL, natural intraepithelial lymphocyte.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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We analyzed subsets relevant to CD, including natural killer (NK)-receptor expressing IELs and killer-cell immunoglobulin-like receptor (KIR)-positive CD8 T cells.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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KLRC1 (NKG2A) was expressed by CCL4 cells, while KLRC2 (NKG2C) was expressed by resident IL7R, TRM(1) and TRM(2) subsets (Extended Data Fig. 5c,d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Inhibitory KIR molecule expression was confined to a small FGFBP2 effector population.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TRM(2) and cycling populations were enriched in ACD, but not TRM(1) cells (Fig. 4f,g).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TRM(2) cells were rare in health, but increased to form 20–40% of CD8 T cells in ACD, which persisted in TCD (Fig. 4h).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Natural IELs were reduced in ACD (Extended Data Fig. 5e).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Cycling CD8 T cells increased to form 2–4% of cells in ACD (Fig. 4i).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Most cycling cells showed a TRM(2) phenotype (Extended Data Fig. 5f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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As TRM(2) CD8 T cells were increased in proportion and proliferating in ACD, we profiled them in depth (Fig. 5a–e and Extended Data Fig. 6).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TRM(2) CD8 T cells showed a CD103 tissue-resident phenotype, high GZMA and absent GZMK expression, along with high expression of CXCR6, activation markers (HLA-DR) and genes expressing co-stimulatory and co-inhibitory molecules (TIGIT, TNFRSF9 (4-1BB), ENTPD1 (CD39) and LAYN (Fig. 4b,c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Comparison of TRM(2) cells in ACD versus TCD showed increased expression of activation markers and increased effector function with IFNG, GZMB and IL32 expression (Extended Data Fig. 5g).Fig.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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5CD8 T cells in CD.a, Pseudotime trajectory of gene expression of tissue-resident CD8 T cell clusters (dataset 1—adult), colored by pseudotime axis (left) and cell cluster (right).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Arrows indicate direction of differentiation.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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b, Pseudotime trajectory, split by disease state, and colored by differentiation branch.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The proportion of CD8 TRM cells differentiating down branches 1 and 2 in each disease state is indicated.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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c, Bubble plot of expression of chemokine, cytokine and TNF family member genes by CD8 T cell clusters in dataset 2 (pediatric).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
d, UMAP plots of CD8 T cells in dataset 2 (pediatric), overlaid with IFNG, CCL20 and FASLG expression.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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e, TCR clonal overlap (Morisita–Horn) between CD8 T cell clusters in dataset 1.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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f, Volcano plot of TRBV segment usage within the TCR repertoire of TRM(2) cells between HCs and CD.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Black, high-frequency TRBV segments used by >1% of total clones; gray, low-frequency TRBV segments used by <1% of total clones.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
g, Volcano plot of TRBV segment gene expression (left) and normalized expression of TRBV28 (right) in bulk RNA-seq data from sorted intraepithelial CD8 T cells (dataset 3; HCs n = 3, ACD n = 4, TCD n = 3, potential CD n = 2).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
h, Volcano plot of TRBV segment usage (left), and proportion of unique CDR3β clonotypes (right above) and proportion of top 100 most common clonotypes (right, below) using the TRBV28 V segment in bulk TCR-seq of CD8 mucosal T cells in HCs and CD (dataset 4; HCs n = 8, ACD n = 7, TCD n = 5).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
f, Negative binomial model without multiple comparisons.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
g, Negative binomial model with Benjamini–Hochberg multiple testing.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h, One-way analysis of variance with Holm–Sidak’s multiple-comparisons test.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
a, Pseudotime trajectory of gene expression of tissue-resident CD8 T cell clusters (dataset 1—adult), colored by pseudotime axis (left) and cell cluster (right).
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Arrows indicate direction of differentiation.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
b, Pseudotime trajectory, split by disease state, and colored by differentiation branch.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
The proportion of CD8 TRM cells differentiating down branches 1 and 2 in each disease state is indicated.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
c, Bubble plot of expression of chemokine, cytokine and TNF family member genes by CD8 T cell clusters in dataset 2 (pediatric).
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
d, UMAP plots of CD8 T cells in dataset 2 (pediatric), overlaid with IFNG, CCL20 and FASLG expression.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
e, TCR clonal overlap (Morisita–Horn) between CD8 T cell clusters in dataset 1.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
f, Volcano plot of TRBV segment usage within the TCR repertoire of TRM(2) cells between HCs and CD.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Black, high-frequency TRBV segments used by >1% of total clones; gray, low-frequency TRBV segments used by <1% of total clones.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
g, Volcano plot of TRBV segment gene expression (left) and normalized expression of TRBV28 (right) in bulk RNA-seq data from sorted intraepithelial CD8 T cells (dataset 3; HCs n = 3, ACD n = 4, TCD n = 3, potential CD n = 2).
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
h, Volcano plot of TRBV segment usage (left), and proportion of unique CDR3β clonotypes (right above) and proportion of top 100 most common clonotypes (right, below) using the TRBV28 V segment in bulk TCR-seq of CD8 mucosal T cells in HCs and CD (dataset 4; HCs n = 8, ACD n = 7, TCD n = 5).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
f, Negative binomial model without multiple comparisons.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
g, Negative binomial model with Benjamini–Hochberg multiple testing.
|
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