IFN-g-Stimulated Mesenchymal Stromal Cells Acquire the Ability To Cross-Present Exogenous Soluble Antigens and Lead to an Effective Immune Response.

Abstract

Antigen cross-presentation is the mechanism by which exogenous antigens can be presented by major histocompatibility complex (MHC) class I molecules to CD8+ T cells. This process is efficiently performed by professional antigen presenting cells (APC) such as dendritic cells and macrophages. Recently, we and others have shown that IFN-g enables the upregulation of the expression of MHC class I & II molecules by marrow-derived Mesenchymal Stromal Cells (MSCs) and that MHC II-mediated antigen presentation can lead to cell-mediated protective immunity to xenoantigens [Stagg et al., Blood March 2006]. These findings led us to investigate whether MSCs also possess the ability to cross-present antigens via MHC class I. Using antigen presentation assays performed on murine MSC in the presence of MHC class I-restricted ovalbumin (OVA)-specific CD8+ T hybridoma cells or purified primary CD8+ T lymphocytes from OT1 transgenic mice, we demonstrated that MSC can robustly and effectively cross-present exogenous antigens via MHC class I molecules upon IFN-g pre-treatment in a manner comparable to professional APCs like macrophages. Use of transporter associated with antigen processing (TAP-1)-deficient mice and proteasome inhibitors suggested a MHC class I machinery-dependent pathway. Cross-presentation by IFN-g-activated MSC was also observed to be suppressed by TGF-b and regulated by cell density. In vivo, IFN-g-treated, OVA-pulsed MSCs administered to normal C57Bl/6 mice led to an effective OVA-specific, T cell cytotoxic immune response, leading to the rejection of OVA-expressing EG7 lymphoma cells. In conclusion, our findings suggest that cross-presentation properties of MSC could play a role in their effectiveness as conditional APCs in vivo and this property may be exploited as a therapeutic cell-based immune biopharmaceutical for treatment of cancer or infectious disease.