IFN‐γ‐indoleamine‐2,3 dioxygenase acts as a major suppressive factor in 4‐1BB‐mediated immune suppression in vivo

It has been reported that 4‐1BB triggering in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)‐specific CD4 + T cells, in which CD8 + T‐derived TGF‐β was involved. Here, we have examined an alternative mechanism for the 4‐1BB‐mediated CD4 + T suppression, as the neutralization of TGF‐β is only effective in rescuing the SEA‐specific recall response at high cellular concentrations. We show that this selective suppression of CD4 + T cells by 4‐1BB triggering in vivo is mediated mainly by induction of indoleamine 2,3‐dioxygenase (IDO) in an IFN‐γ‐dependent manner. SEA‐specific CD4 + T responses were suppressed partly by TGF‐β‐expressing CD8 + T cells, particularly CD11c + CD8 + T cells, but strongly inhibited by dendritic cells (DCs) expressing IDO. IFN‐γ that increased IDO in DCs was produced primarily from CD11c + CD8 + T cells, which were expanded 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‐γ 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‐γ‐dependent IDO induction and partially by TGF‐β.