genes for chemok ines and receptors, including cxcr5, ccr7, ccl19, ccl21, cxcl13 and cxcl14 were enriched specifically within las ( fig. 7l ), as were genes associated with s3 stromal cells, and pro - inflammatory stroma seen in inflammatory bowel disease ( fig. 7m ). we examined the expression of chemok ines, cytokines and tumor necrosis factor ( tnf ) superfamily members, as well as receptor – ligand coexpression, within regions in the spatial transcriptomics dataset ( fig. 8a, b and supplementary fig. 8 ). signaling pathway expression was region dependent, indicating highly localized mucosal signaling circuits ( fig. 8a ). within cd - specific las, chemok ine signaling circuits involving cxcr5 – cxcl13, ccr7 – ccl19, cxcr4 and integrins itgb2 and itgam were upregulated ( fig. 8a and supplementary fig. 8a, b ). tnf superfamily receptor – ligand pathways were upregulated in las, including tnf, lymphotoxins a and b, cd40, tnfrsf8 ( cd30 ), tnfrsf6b, tnfrsf18 ( gitr ) and tnfrsf4 ( ox40 ) ( supplementary fig. 8c, d ). there was also evidence of il2 and il21 signaling, as well as possible involvement of il23a and il26 pathways ( supplementary fig. 9e, f ). las found in cd were enriched with signaling pathways involving cxcr4, cxcr5 and cxcl13 ( figs. 7l and 8a, b ). single - cell examination of cxcl13, ccr7 and itgb2 signaling interactions in dataset 1 implicated t fh - like cd4 t cell, b cell and myeloid cell interactions as drivers of these signaling pathways in las ( fig. 8b ). villus tip regions, demonstrated region - specific activation of t cell and immune-related pathways, including increased expression of il15, il18, ifng and il32, and interactions including cxcr6 – cxcl16, ccr9 – ccl25, dpp4 – ada and hla - e interactions with klrc2 and klrd1 ( fig. 8a and supplementary fig. 8 ). there was also high expression of tnf superfamily members associated with apoptotic pathways, including faslg, tnfsf10 ( trail ), tnfsf11 ( rankl ), tnfsf12 ( tweak ) and tnfsf13 ( april ) interactions. examination of single - cell signaling pathways implicated cd8 t cells in chemok ine and type ii interferon signaling, including ccr9 – ccl25 axis interactions between progenitor ecs and cycling cd8 t cells ( fig. 8b ). wnt signaling pathways were enriched in telocyte - rich areas and neighboring villus structures ( fig. 8a ). such morphogen gra dien ts may shape villus structure and morphology, perhaps driven by subepithelial telocytes. to understand how genetic susceptibility can drive cd inflammatory responses, we examined putative genome-wide association study ( gwas ) candidate gene expression in spatial regions. villus, telocyte - rich and la regions showed enriched expression of multiple gwas candidates ( extended data fig. 10a ). expression of mmp9, ctla4, icos, itga4, gpr183, il21 and il21r was enriched within cd - specific la regions ( extended data figs. 9e and 10a ), while il2ra, ccr1, xcr1, tnfsf11 ( rankl ) and tnfrsf9 ( cd137, 4 - 1bb ) were increased in telocyte - rich regions. scrna - seq data were examined for cell - type - specific expression of cd genetic susceptibility loci. gwas candidate genes were most prominent in t cell subsets ( extended data fig. 10b ), with the highest signal enrichment in cycling cd8 t cells. specific putative gwas candidate genes drove these associations ( extended data fig. 10c ), with t fh - like cd4 t cells expressing the il21, ptpn2, itga4, cd28 and icos and t rm ( 2 ) cd8 t cells expressing cxcr6, tnfrsf9 and tnfrsf14, and showing cd - related changes in stat expression ( extended data fig. 10d ). cell - type - specific gene expression patterns were recapitulated in dataset 2 ( extended data fig. 10e ). this multi - omics study provides an integrated single - cell transcriptomic and proteomic assessment of intestinal immune, epithelial and parenchymal cell populations in adult and pediatric cd, contextualized through integration with spatial transcriptomics analysis. our results show that perturbations of immune and epithelial cell states are spatially localized within distinc t mucosal niches. disease-associated cell types, including gluten - specific t fh - like cd4 t cells and cd8 t rm cells, occupy distinc t la and villus niches, respectively, with cell – cell interactions best understood through spatial colocalization ( fig. 8c ). the application of receptor – ligand analyses implicates broader cytokine and chemok ine perturbations in cd than those described previously, including il - 32, cxcl13, ccl19, cxcl16, cxcl8 and ccl25. our understanding of human duodenal lymphoid structures is incomplete. isolated gut lymphoid structures may act as immune - inductive sites. in cd, it remains unclear where the immune response to gluten is primed, or where subsequent antigen presentation occurs. both myeloid and b cell lineages have been posited as relevant antigen - presenting cells ( apcs ) in cd. the discovery of highly localized las where b cells and ( likely gluten - specific ) t fh cd4 t cells are co - located implicates these sites in gluten peptide antigen presentation. several aspects of the mucosal epithelial and immune response remained perturbed despite a gfd. these findings help explain the observation that subtle abnormalities in duodenal biopsy samples remain despite treatment, with reduced villus height / crypt depth ratios on morphometric analysis. whether this represents subclinical inflammation from ongoing low - level antigen exposure, slow mucosal healing or a long - term ( perhaps epigenetic ) response to prior inflammation is unclear. participants often report ongoing symptoms despite a gfd, and this epithelial and immunological ‘ scar ’ from prior inflammation could underpin this, representing a therapeutic target. intestinal tissue - resident cd8 t cell perturbations, including increases in t rm ( 2 ) populations, persisted despite gfd treatment. therefore, this cd8 t rm ( 2 ) state may represent a distinc t t cell fate, rather than an activated phenotype alone. t rm cells are long - lived memory populations that persist as immunological sentinels in barrier tissues, and this result is consistent with prior work showing a permanent reshaping of γδt cell - resident populations following cd - driven inflammation. cd8 t cell populations exhibited changes in tcr repertoire, a finding validated in multiple datasets. these tcr repertoire changes, along with upregulation of tcr signaling gene sets, may indicate that tcr - dependent activation is relevant in cd, involving a separate mechanism to previously described nkg2c / nkg2d pathways, and invoke the possibility of tcr - targeted disease therapies. il - 15 and nk cell receptor signaling could lead to a reduction in tcr activation threshold, which could enable recognition of low - affinity antigens, either self - antigens or those of microbial or dietary origin. the persistence of cd8 t rm ( 2 ) cells in tcd could represent ongoing antigen exposure. there is a series of enterocyte transcriptional states in the human small intestine, with absorptive cellular machinery generally limited to mature ecs, consistent with murine studies. the shift to progenitor states in cd may increase ccl25 expression, implicating the ccl25 – ccr9 axis in disease. this shift toward progenitor states underpins cd - associated malabsorption, beyond reduction in intestinal surface area. in contrast to the term ‘ villus atrophy ’, we observe that the cd epithelium is hyperproliferative, and so the loss of villus structures requires additional explanation. spatial transcriptomics data indicate specific regions responsible for wnt signaling, and we hypothesize that cd inflammation drives morphogen signaling shifts causing mucosal remodeling. these morphogen responses may not be cd specific, and may underpin histological similarities seen with mimics such as environmental enteropathy, monog enic enteropathies and olmesartan enteropathy.