Downregulation of Antigen-Presenting Cell Functions After Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice

• Published in: Blood 1999-12, Vol.94 (12), p.4347-4357
• Main Authors: Muraille, Eric, Andris, Fabienne, Pajak, Bernard, Wissing, K. Martin, De Smedt, Thibaut, Desalle, Fabrice, Goldman, Michel, Alegre, Maria-Luisa, Urbain, Jacques, Moser, Muriel, Leo, Oberdan
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigen Presentation - drug effects; Antigen Presentation - immunology; Biological and medical sciences; CD3 Complex - immunology; Down-Regulation - drug effects; Down-Regulation - immunology; Immunomodulators; Immunosuppression; Medical sciences; Mice; Pharmacology. Drug treatments; T-Lymphocytes - immunology; Transplantation Immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.12.4347

Antibodies against CD3ɛ 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-CD3ɛ 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-CD3ɛ–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-CD3ɛ 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-CD3ɛ antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3ɛ monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3ɛ–induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3ɛ antibodies downregulate immune responses.