T cell mediated impairment of epithelial integrity in Crohn's disease

T lymphocytes play a major role in intestinal homeostasis, with a particular impact on the balance between self-renewal and differentiation of intestinal epithelial cells (IECs). In Crohns disease (CD) patients, the intestinal mucosa is inflamed, epithelium permeability is increased, and IECs present compositional and functional defects. The role of T lymphocytes interactions with IECs in the physiopathology of CD remains in question. Here, we use a three-dimensional human autologous coculture model between purified intestinal organoids derived from primary tissues of CD and non-inflammatory control patients, and mucosal T lymphocytes extracted from the same location. We show that while in homeostatic context T cells support the proliferation and differentiation balance of organoids, mucosal T lymphocytes from CD patients present a high cytotoxicity against IECs. Importantly, this cytotoxicity is a persistent defect overtime in culture. Organoids also show defective intestinal stem cells (ISCs) proliferation and morphological changes. Single cell RNA sequencing after coculture highlights a general response of T cells to the epithelial microenvironment, and more particularly, an increase activation of a pro-inflammatory CD8+ T cells effector population in CD patients compared to controls. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/621219v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@78453aorg.highwire.dtl.DTLVardef@8f484org.highwire.dtl.DTLVardef@1ed0934org.highwire.dtl.DTLVardef@f75094_HPS_FORMAT_FIGEXP M_FIG C_FIG