IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells.
CD4(+) T regulatory type 1 (Tr1) cells suppress Ag-specific immune responses in vitro and in vivo. Although IL-10 is critical for the differentiation of Tr1 cells, the effects of other cytokines on differentiation of naive T cells into Tr1 cells have not been investigated. Here we demonstrate that endogenous or exogenous IL-10 in combination with IFN-alpha, but not TGF-beta, induces naive CD4(+) T cells derived from cord blood to differentiate into Tr1 cells: IL-10(+)IFN-gamma(+)IL-2(-/low)IL-4(-). Naive CD4(+) T cells derived from peripheral blood require both exogenous IL-10 and IFN-alpha for Tr1 cell differentiation. The proliferative responses of the Tr1-containing lymphocyte populations, following activation with anti-CD3 and anti-CD28 mAbs, were reduced. Similarly, cultures containing Tr1 cells displayed reduced responses to alloantigens via a mechanism that was partially mediated by IL-10 and TGF-beta. More importantly, Tr1-containing populations strongly suppressed responses of naive T cells to alloantigens. Collectively, these results show that IFN-alpha strongly enhances IL-10-induced differentiation of functional Tr1 cells, which represents a first major step in establishing specific culture conditions to generate T regulatory cells for biological and biochemical analysis, and for cellular therapy to induce peripheral tolerance in humans.
Levings
M K
MK
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
Sangregorio
R
R
Galbiati
F
F
Squadrone
S
S
de Waal Malefyt
R
R
Roncarolo
M G
MG
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D004338:Drug Combinations; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000097:blood / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D007739:L Cells; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004338:Drug Combinations; D016898:Interferon-alpha; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D016753:Interleukin-10