Role of the B7RP-1/ICOS Pathway in Renal Tubular Epithelial Antigen Presentation to CD4+ Th1 and Th2 Cells

Abstract

Background: IFN-γ-stimulated renal tubular epithelial cells (TECs) can present foreign protein antigen to T cells when stimulated with IFN-γ. TECs normally do not express B7, the ligand for the classical T-cell costimulatory molecule CD28, but express B7RP-1, the ligand of the inducible costimulator (ICOS). Methods: Flow cytometry was used to demonstrate expression of B7RP-1 on TECs, and expression of ICOS on A.E7 (Th1 clone) and D10.G4 (Th2 clone) cells. Using gene arrays, ELISA, and protein arrays, we examined the cytokine response of Th1 and Th2 subsets of CD4+ T cells in antigen presentation by IFN-γ-stimulated murine primary TECs. Results: In the presence of a specific foreign protein antigen, MHC-II-positive TECs induced clustering and a marked production of IFN-γ (A.E7) or IL-4 (D10.G4) by T cells. Blockade of the B7RP-1/ICOS pathway with specific monoclonal antibodies (mAbs) lead to a further increase in IFN-γ production by A.E7 cells, and a further increase in IL-4 production by D10.G4 cells as detected by gene array and ELISA. Protein arrays demonstrated an increase in Th2 cytokine levels upon blockade of the B7RP-1/ICOS pathway. Conclusions: These data show that the B7RP-1/ICOS interaction inhibits Th1 and Th2 T-cell responses in the setting of foreign antigen presentation by renal TECs. This inhibitory pathway may therefore serve as a negative feedback mechanism to inhibit immune-mediated tubulointerstitial renal disease.