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1.
Immunity ; 55(12): 2336-2351.e12, 2022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36462502

RESUMEN

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) revealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue remodeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for organoid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD.


Asunto(s)
Colitis , Mucosa Intestinal , Animales , Cicatrización de Heridas , Células Epiteliales/metabolismo , Epitelio , Modelos Animales de Enfermedad
2.
Mucosal Immunol ; 17(1): 81-93, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37952848

RESUMEN

Commensal-specific clusters of differentiation (CD)4+ T cells are expanded in patients with inflammatory bowel disease (IBD) compared to healthy individuals. How and where commensal-specific CD4+ T cells get activated is yet to be fully understood. We used CBir1 TCR-transgenic CD4+ T cells, specific to a commensal bacterial antigen, and different mouse models of IBD to characterize the dynamics of commensal-specific CD4+ T-cells activation. We found that CBir1 T cells proliferate following intestinal damage and cognate antigen presentation is mediated by CD11c+ cells in the colon-draining mesenteric lymph nodes. Using assay for transposase-accessible chromatin sequencing and flow cytometry, we showed that activated CBir1 T cells preferentially acquire an effector rather than regulatory phenotype, which is plastic over time. Moreover, CBir1 T cells, while insufficient to initiate intestinal inflammation, contributed to worse disease outcomes in the presence of other CD4+ T cells. Our results suggest that the commensal-specific T-cell responses observed in IBD exacerbate rather than initiate disease.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Linfocitos T , Ratones , Animales , Humanos , Intestinos , Diferenciación Celular , Citometría de Flujo , Linfocitos T CD4-Positivos
3.
JCI Insight ; 8(4)2023 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-36810249

RESUMEN

Helicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. To deeply characterize the host-microbiota environment in H. pylori-infected (HPI) stomachs, we collected human gastric tissues and performed metagenomic sequencing, single-cell RNA-Seq (scRNA-Seq), flow cytometry, and fluorescent microscopy. HPI asymptomatic individuals had dramatic changes in the composition of gastric microbiome and immune cells compared with noninfected individuals. Metagenomic analysis uncovered pathway alterations related to metabolism and immune response. scRNA-Seq and flow cytometry data revealed that, in contrast to murine stomachs, ILC2s are virtually absent in the human gastric mucosa, whereas ILC3s are the dominant population. Specifically, proportion of NKp44+ ILC3s out of total ILCs were highly increased in the gastric mucosa of asymptomatic HPI individuals, and correlated with the abundance of selected microbial taxa. In addition, CD11c+ myeloid cells and activated CD4+ T cells and B cells were expanded in HPI individuals. B cells of HPI individuals acquired an activated phenotype and progressed into a highly proliferating germinal-center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria. Our study provides a comprehensive atlas of the gastric mucosa-associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.


Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Humanos , Animales , Ratones , Inmunidad Innata , Análisis de Expresión Génica de una Sola Célula , Estómago , Mucosa Gástrica , Células Plasmáticas
4.
Nat Commun ; 13(1): 828, 2022 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-35149721

RESUMEN

The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.


Asunto(s)
Intestinos/metabolismo , Transcriptoma , Cicatrización de Heridas , Animales , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Células Epiteliales , Femenino , Mucosa Intestinal/metabolismo , Intestinos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Transducción de Señal
5.
Nat Commun ; 11(1): 2049, 2020 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-32341343

RESUMEN

ILCs and T helper cells have been shown to exert bi-directional regulation in mice. However, how crosstalk between ILCs and CD4+ T cells influences immune function in humans is unknown. Here we show that human intestinal ILCs co-localize with T cells in healthy and colorectal cancer tissue and display elevated HLA-DR expression in tumor and tumor-adjacent areas. Although mostly lacking co-stimulatory molecules ex vivo, intestinal and peripheral blood (PB) ILCs acquire antigen-presenting characteristics triggered by inflammasome-associated cytokines IL-1ß and IL-18. IL-1ß drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-κB-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4+ T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-ß. Our results suggest that circulating and tissue-resident ILCs have the intrinsic capacity to respond to the immediate cytokine milieu and regulate local CD4+ T-cell responses, with potential implications for anti-tumor immunity and inflammation.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Citocinas/inmunología , Inmunidad Innata , Linfocitos/inmunología , Animales , Presentación de Antígeno , Linfocitos T CD4-Positivos/inmunología , Neoplasias del Colon/inmunología , Humanos , Inflamasomas/inmunología , Interleucina-18/inmunología , Interleucina-1beta/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Leucocitos Mononucleares/inmunología , Ratones
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