Modulation of cord blood CD8 T-cell effector differentiation by TGF- 1 and 4-1BB costimulation

Transforming growth factor1 (TGF1), 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 CTLmediated antitumor immune responses. We investigated whether TGF1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8 T cells into effector CTL cells. TGF1 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. TGF1–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 TGF1, suggesting that 4-1BB effects were at the level of TGF1 signaling. 4-1BB effects on the TGF1–mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was upor 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 TGF1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF1–mediated suppression. (Blood. 2005;105:274-281)