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(+)Reg(c)) are generated from cocultures of peripheral blood CD8(+)T cells and bone-marrow-derived stromal cells. When cell-to-cell interactions occur, CD8(+)Reg(c) strongly inhibit lymphocyte proliferation at a ratio of 1:1 to 1:100 between CD8(+)Reg(c) and responding lymphocytes. Phenotypic analysis indicated that CD8(+)Reg(c) 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-beta, and prostaglandin E(2) are not involved in the generation of CD8(+)Reg(c) from CD8(+) precursors or in the immunosuppressive mechanism mediated by CD8(+)Reg(c) on lymphocyte proliferation. Cyclosporin A (CSA) slightly downregulated generation of CD8(+)Reg(c) indicating that only a small fraction of precursors of CD8(+)Reg(c) are sensitive to this immune-suppressive drug. Along this line, treatment of effector CD8(+)Reg(c)with CSA does not affect their immunosuppressive effect, indicating that the molecular mechanism of CD8(+)Reg(c)-mediated regulation is independent of the function of CSA biochemical target molecules.