Role of bone marrow stromal cells in the generation of human CD8+ regulatory T cells

Fibroblast-like stromal cells exert a strong inhibitory effect on lymphocyte proliferation, both directly by interacting with responding lymphocytes and indirectly by inducing the generation of regulatory T cells. Indeed, upon triggering via the CD3/TCR complex, highly effective CD8+regulatory cells (CD8+Regc) are generated from cocultures of peripheral blood CD8+T cells and bone-marrow-derived stromal cells. When cell-to-cell interactions occur, CD8+Regc strongly inhibit lymphocyte proliferation at a ratio of 1:1 to 1:100 between CD8+Regc and responding lymphocytes. Phenotypic analysis indicated that CD8+Regc are CD25+CD28+ and express low levels of mRNA for Foxp3 but they do not bear CTLA4 and glucocorticoid-induced tumor necrosis factor receptor antigens. Soluble mediators such as interleukin-10, transforming growth factor-β, and prostaglandin E2 are not involved in the generation of CD8+Regc from CD8+ precursors or in the immunosuppressive mechanism mediated by CD8+Regc on lymphocyte proliferation. Cyclosporin A (CSA) slightly downregulated generation of CD8+Regc indicating that only a small fraction of precursors of CD8+Regc are sensitive to this immune-suppressive drug. Along this line, treatment of effector CD8+Regcwith CSA does not affect their immunosuppressive effect, indicating that the molecular mechanism of CD8+Regc-mediated regulation is independent of the function of CSA biochemical target molecules.