Interferon-γ-stimulated marrow stromal cells:: a new type of nonhematopoietic antigen-presenting cell

Several studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFN gamma)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalburnin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalburnin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFN gamma-treated MSCs could further activate in vitro ovalburnin-specific primary transgenic CD4(+) T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFN gamma-treated MSCs, they developed antigen-specific cytotoxic CD8(+) T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFN gamma-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses.