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 tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-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 was observed in 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 revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal 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, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.
Mittler
R S
RS
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Immunology and Transplantation, Seattle, Washington 98121, USA. Rmittler26@aol.com
Bailey
T S
TS
Klussman
K
K
Trailsmith
M D
MD
Hoffmann
M K
MK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics; D000917:Antibody Formation; D015703:Antigens, CD; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D007108:Immune Tolerance; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014301:Trinitrobenzenes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C020529:TNP-ficoll; C505715:Tnfrsf9 protein, mouse; D014301:Trinitrobenzenes; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D005362:Ficoll