Epithelial cells prime the immune response to an array of gut‐derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor‐β

Abstract

SummaryHumans and other mammals coexist with a diverse array of microbes colonizing the intestine, termed the microflora. The relationship is symbiotic, with the microbes benefiting from a stable environment and nutrient supply, and the host gaining competitive exclusion of pathogens and continuously maintenance of the gut immune homeostasis. Here we report novel crosstalk mechanisms between the human enterocyte cell line, Caco2, and underlying human monocyte-derived DC in a transwell model where Gram-positive (G + ) commensals prevent Toll-like receptor-4 (TLR4)-dependent Escherichia coli-induced semimaturation in a TLR2-dependent fashion. These findings add to our understanding of the hypo-responsiveness of the gut epithelium towards the microflora. Gut DC posses a more tolerogenic phenotype than conventional DC. Here we show that Caco2 spent medium (SM) induces tolerogenic DC with lower expression of maturation markers, interleukin (IL)-12p70, and tumour necrosis factor-a when matured with G + and Gram-negative (G -) commensals, while IL-10 production is enhanced in DC upon encountering G + commensals and reduced upon encountering G -bacteria. The Caco2 SM-induced tolerogenic phenotype is also seen in DC priming of naive T cells with elevated levels of transforming growth factor-b (TGF-b) and markedly reduced levels of bacteria-induced interferon-c production. Caco2 cell production of IL-8, thymic stromal lymphopoietin (TSLP) and TGF-b increases upon microbial stimulation in a strain dependent manner. TSLP and TGF-b co-operate in inducing the tolerogenic DC phenotype but other mediators might be involved.

Probiotics and immunity

“…There are, however, studies showing that probiotics and other nonpathogenic LAB or components thereof strain-specifi cally affect the production of the chemokine IL-8 and of proinfl ammatory cytokines by intestinal epithelial cells. [42][43][44][45][46][47][48] This ability is further modulated by the presence of leukocytes on the basolateral part of the culture plates. 49 In turn, experiments where bacteria are added to the apical side and DCs to the basolateral side of an intestinal epithelial cell monolayer show that the presence of intestinal epithelium affects the ability of probiotic and other bacteria to induce DC maturation, and particularly the ratio of IL-10 to IL-12 that these DCs release.…”

“…49 In turn, experiments where bacteria are added to the apical side and DCs to the basolateral side of an intestinal epithelial cell monolayer show that the presence of intestinal epithelium affects the ability of probiotic and other bacteria to induce DC maturation, and particularly the ratio of IL-10 to IL-12 that these DCs release. 41,42 In addition, the small fraction of DCs that directly sample bacteria by extending dendrites across the intestinal epithelial layer are activated to a different extent than those that only come into contact with soluble mediators produced by epithelial cells that have encountered these bacteria. 41 Interestingly, DCs treated with supernatant fractions of epithelial cell-bacteria cocultures or of epithelial cells alone were found to preferentially drive Th2 or regulatory T-cell responses, that is, to induce a "mucosal" DC phenotype, even though peripheral MDDCs were used in these experiments.…”

“…41 Interestingly, DCs treated with supernatant fractions of epithelial cell-bacteria cocultures or of epithelial cells alone were found to preferentially drive Th2 or regulatory T-cell responses, that is, to induce a "mucosal" DC phenotype, even though peripheral MDDCs were used in these experiments. 41,42 The production of TGF-β and thymic stromal lymphopoietin by intestinal epithelial cells has been implicated in the induction of this tolerogenic DC phenotype. 42,50 …”

“…41,42 The production of TGF-β and thymic stromal lymphopoietin by intestinal epithelial cells has been implicated in the induction of this tolerogenic DC phenotype. 42,50 …”

Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin–Conditioned Dendritic Cells Induce Regulatory T-Cell Differentiation and Protection of NOD Mice Against Diabetes

“…TSLP, a member of the IL-7 cytokine family, is preferentially expressed by epithelial cells mainly in the lung, skin, and gut (27,28). Recently, clues for a function of TSLP in humans came from two observations.…”