suppressive factor in 4-1BB-mediated immune suppression in vivo

It has been reported that 4-1BB trigger- ing in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)-specific CD4 T cells, in which CD8 T-derived TGF- was in- volved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4 T sup- pression, as the neutralization of TGF- is only effec- tive in rescuing the SEA-specific recall response at high cellular concentrations. We show that this selec- tive suppression of CD4 T cells by 4-1BB triggering in vivo is mediated mainly by induction of indoleam- ine 2,3-dioxygenase (IDO) in an IFN--dependent manner. SEA-specific CD4 T responses were sup- pressed partly by TGF--expressing CD8 T cells, particularly CD11cCD8 T cells, but strongly in- hibited by dendritic cells (DCs) expressing IDO. IFN- that increased IDO in DCs was produced pri- marily from CD11cCD8 T cells, which were ex- panded selectively by 4-1BB stimulation. CD4, CD8, and plasmacytoid DCs exerted a similar suppressive activity toward the SEA-specific CD4 T cells. Neutralization of IFN- or IDO activity in vivo largely reversed the 4-1BB-mediated CD4 T suppression. Collectively, these data indicate that 4-1BB-dependent suppression of SEA-specific CD4 T responses was mediated mainly by IFN--depen- dent IDO induction and partially by TGF-. J. Leu- koc. Biol. 85: 000-000; 2009.