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Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

ABSTRACT: Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

SUBMITTER: Hammoudi N

PROVIDER: S-EPMC9685428 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Hammoudi Nassim N Hamoudi Sarah S Bonnereau Julie J Bottois Hugo H Pérez Kevin K Bezault Madeleine M Hassid Déborah D Chardiny Victor V Grand Céline C Gergaud Brice B Bonnet Joëlle J Chedouba Leila L Tran Minh My-Linh ML Gornet Jean-Marc JM Baudry Clotilde C Corte Hélène H Maggiori Léon L Toubert Antoine A McBride Jacqueline J Brochier Camille C Neighbors Margaret M Le Bourhis Lionel L Allez Matthieu M

Frontiers in immunology 20221110

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively corr ...[more]

PMID: 36439157

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Project description:Abstract Objectives Crohn's disease (CD) initiation and pathogenesis are believed to involve an environmental trigger in a genetically susceptible person that results in an immune response against commensal gut bacteria, leading to a compromised intestinal epithelial barrier and a cycle of inflammation. However, it has been difficult to study the contribution of all factors together in a physiologically relevant model and in a heterogenous patient population. Methods We developed an autologous colonic monolayer model that incorporated the immune response from the same donor and a commensal bacteria, Faecalibacterium prausnitzii. Two‐dimensional monolayers were grown from three‐dimensional organoids generated from intestinal biopsies, and the epithelial integrity of the epithelium was measured using transepithelial electrical resistance. We determined the effect of immune cells alone, bacteria alone and the co‐culture of immune cells and bacteria on integrity. Results Monolayers derived from CD donors had impaired epithelial integrity compared to those from non‐inflammatory bowel disease (IBD) donors. This integrity was further impaired by culture with bacteria, but not immune cells, despite a higher frequency of inflammatory phenotype peripheral T cells in CD donors. Variability in epithelial integrity was higher in CD donors than in non‐IBD donors. Conclusion We have developed a new autologous model to study the complexity of CD, which allows for the comparison of the barrier properties of the colonic epithelium and the ability to study how autologous immune cells directly affect the colonic barrier and whether this is modified by luminal bacteria. This new model allows for the study of individual patients and could inform treatment decisions. We developed an autologous model to study epithelial integrity in human Crohn's disease (CD). We cultured immune cells and the commensal bacterium, Faecalibacterium prausnitzii, with patient‐matched epithelial monolayers generated from three‐dimensional organoids derived from intestinal biopsies. We showed inherent differences in integrity in monolayers from CD patients and a further reduction upon culture with bacteria but not immune cells.

Dataset Information

Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Publications

Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

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