Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy

The 4-1BB receptor (CDw137), a member of the turner necrosis factor recepto r superfamily, has been shown to costimulate the activation of T cells. Her e we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus -dependent antibody production by B cells. Injection of anti-4-1BB mAbs int o mice being immunized with cellular or soluble protein antigens induced lo ng-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti- 4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition w as observed ill mice lacking functional CD8(+) T cells, indicating that CD8 (+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity rev ealed that suppression could not be adoptively transferred with T cells fro m anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep re d blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with nor mal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized , anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhib ited a normal humoral immune response against SRBC after transfer, demonstr ating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.