Downregulation of antigen-presenting cell functions after administration of mitogenic anti-CD3 monoclonal antibodies in mice.
Antibodies against CD3epsilon are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3epsilon antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3epsilon-treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3epsilon treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3epsilon antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3epsilon monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3epsilon-induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3epsilon antibodies downregulate immune responses.
Muraille
E
E
Laboratoire de Physiologie Animale, Département de Biologie Moléculaire, Université Libre de Bruxelles, Gosselies, Belgium.
Andris
F
F
Pajak
B
B
Wissing
K M
KM
De Smedt
T
T
Desalle
F
F
Goldman
M
M
Alegre
M L
ML
Urbain
J
J
Moser
M
M
Leo
O
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D014181:Transplantation Immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex