D40-Mediated Immune-Nonimmune Cell Interactions nduce Mucosal Fibroblast Chemokines Leading to T-Cell ransmigration

C F h e t b c ackground & Aims: The CD40 pathway is a key meditor of inflammation and autoimmunity. We investiated cell adhesion molecule (CAM) up-regulation and hemokine production by CD40-positive human intestial fibroblasts (HIF) and microvascular endothelial cells HIMEC) induced by CD40 ligand (CD40L)-positive T cells nd soluble CD40L and their effect on T-cell adhesion nd transmigration. Methods: Expression of CD40, D40L, and CAM was assessed by immunohistochemstry, confocal microscopy and flow cytometric analysis, nd chemokine production using enzyme-linked immuosorbent assay. Calcein-labeled T cells were used to ssay HIF adhesion and Transwell HIMEC transmigraion. Results: Ligation of CD40-positive HIF and HIMEC y CD40L-positive T cells or soluble CD40L induced p-regulation of CAM expression as well as interleukin-8 nd RANTES production. The specificity of these reponses was shown by inhibition with a CD40L blocking ntibody and by CD40 signaling-dependent p38 mitoen-activated protein kinase phosphorylation. On CD40 igation, HIF increased their T-cell binding capacity and enerated chemoattractants able to induce T-cell migraion through HIMEC monolayers. Conclusions: Activation f the CD40/CD40L system in the gut mucosa may rigger a self-sustaining loop of immune-nonimmune ell interactions leading to an antigen-independent inux of T cells that contributes to chronic inflammation.