MHC class II upregulation and colocalization with Fas in experimental models of immune-mediated bone marrow failure

Objective. To test the hypothesis that gamma-interferon (IFN-gamma) promotes major histocompatibility complex (MHC) class II expression on bone marrow (BM) cell targets that facilitate T-cell-mediated BM destruction in immune-mediated BM failure. Materials and Methods. Allogeneic lymph node (LN) cells were infused into MHC- or minor histocompatibility antigen-mismatched hosts to induce BM failure. MHC class II and Fas expression and cell apoptosis were analyzed by flow cytometry. MHC class II-Fas colocalization was detected by ImageStream Imaging Flow Cytometry and other cell-to-cell associations were visualized by confocal microscopy. T-cell mediated BM cell apoptosis and effects of IFN-gamma on MHC class II-Fas colocalization on normal BM cells were studied using cell culture in vitro followed by conventional and imaging flow cytometry. Results. BM failure animals had significantly upregulated MHC class II expression on CD4(-)CD8(-)CD11b(-)CD415R(-) residual BM cells and significantly increased MHC class II-Fas colocalization on BM CD150(+) and CD34(+) hematopoietic cells. MHC class II(+)Fas(+) BM cells were closely associated with CD4(+) T cells in the BM of affected animals, and they were significantly more responsive to T-cell-mediated cell apoptosis relative to MHC class II(-)Fas(-) BM cells. Infusion of IFN-gamma-deficient LN cells into minor histocompatibility antigen-mismatched recipients resulted in no MHC class II-Fas upregulation and no clinically overt BM failure. Treatment with recombinant IFN-gamma significantly increased both MHC class II-Fas coexpression and colocalization on normal BM cells. Conclusions. Elevation of the inflammatory cytokine IFN-gamma stimulated MHC class H expression and MHC class H-Fas colocalization, which may facilitate T-cell mediated cell destruction. Published by Elsevier Inc. on behalf of the ISEH - Society for Hematology and Stem Cells.