Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-{beta}.
T cells with immunoregulatory function have been described in human and mouse systems. In both systems these cells can be differentiated either in the thymus or from peripheral T cells. To date, more progress has been made in the study of murine regulatory T cells, because it has been very difficult to isolate human regulatory T cells of sufficient purity and in sufficient numbers to permit detailed examinations of their biochemistry. We report in this study that human T cells with regulatory function can be differentiated in vitro from naive (CD4(+)CD45RA(+)) cord blood or peripheral T cells by stimulation with anti-CD3 and anti-CD28 in the presence of TGF-beta. Cells derived in this manner express a surface phenotype (CD25(+), CD122(+), HLA-DR(+), glucocorticoid-induced TNF receptor-related gene(+), CD103(+), CTLA-4(+)) described for human and mouse regulatory T cells and express protein and message for the transcription factor forkhead/winged helix transcription factor (FOXP3). They produce primarily TGF-beta and IL-10, with lesser amounts of IFN-gamma and IL-13, when stimulated through their TCRs and are capable of inhibiting cytokine production and proliferation by stimulated naive T cells. Unlike Th1 and Th2 cells, these TGF-beta-derived regulatory T cells do not appear to be dependent on the protein kinase Ctheta; pathway of NF-kappaB activation for Ag-induced responses.
Rao
Patricia E
PE
TolerRx, Cambridge, MA 02139, USA. dandp77@earthlink.net
Petrone
Andria L
AL
Ponath
Paul D
PD
D000098:Acetophenones / Q000494:pharmacology; D000328:Adult; D001578:Benzopyrans / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors; D006801:Humans; D016130:Immunophenotyping; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008213:Lymphocyte Activation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D000074121:Protein Kinase C-theta; D012333:RNA, Messenger / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000276:immunology
D000098:Acetophenones; D001578:Benzopyrans; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007527:Isoenzymes; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C085746:rottlerin; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta