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.
Poggi
Alessandro
A
Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy. alessandro.poggi@istge.it
Zocchi
Maria Raffaella
MR
D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016572:Cyclosporine; D015232:Dinoprostone