Abstract

NOD2 mutations are associated with susceptibility to Crohn's Disease and Graft-Versus-Host Disease, two Human disorders related with dysfunctions of Peyer's patches (PP). In Nod2-/- mice transcellular permeability and bacterial translocation are increased in PP. In this study, we show that both anti-CD4⁺ and anti-IFNγ monoclonal antibodies abrogate this phenotype and reduce the expression of TNFR2 and the long isoform of MLCK, thus demonstrating that immune T cells influence the epithelial functions. In turn, intraperitoneal injection of ML-7 (a MLCK inhibitor) normalise the values of CD4⁺ T-cells, IFNγ and TNFα. This reciprocal crosstalk is under the control of the gut microflora as shown by the normalisation of all parameters after antibiotic treatment. TLR2 and TLR4 expression were increased in Nod2^-/- mice under basal conditions and TLR2 and TLR4 agonists induced an increased transcellular permeability in Nod2^+/+ mice. Muramyldipeptide (a Nod2 agonist) or ML-7 were able to reverse this phenomenon.

It thus appears that Nod2 modulates the cross-talk between CD4⁺ T-cells and the epithelium recovering PP and that it down-regulates the pro-inflammatory effect driven by the ileal microflora, likely by inhibiting the TLR pathways.