Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation.
Transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-beta1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-beta1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-beta1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-beta1, suggesting that 4-1BB effects were at the level of TGF-beta1 signaling. 4-1BB effects on the TGF-beta1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-beta1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-beta1-mediated suppression.
Kim
Young-June
YJ
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis 46202-5181, USA.
Stringfield
Teresa M
TM
Chen
Yan
Y
Broxmeyer
Hal E
HE
D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation; D005312:Fetal Blood; D053804:Granzymes; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000906:Antibodies; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D016212:Transforming Growth Factor beta; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D018664:Interleukin-12; D015847:Interleukin-4; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases