IL-2-resistant hyporesponsiveness induced by CD4 mAbs in OKT3-activated human T cells is reversed by CD45RA triggering.
CD4 monoclonal antibodies (mAbs) are potent immunosuppressive agents which have been shown to induce in vivo tolerance to antigens and alloantigens and are presently evaluated in humans in the treatment of autoimmune diseases. In previous studies, we observed that clinical improvement of CD4 mAb-treated psoriasis patients was achieved without depletion of CD4+ lymphocytes and at nonsaturating CD4 mAb concentrations, suggesting a functional blockade of CD4+ lymphocyte responses. In this study, we demonstrate that priming of normal human CD4+ T cells by immobilized OKT3 (iOKT3) in the presence of CD4 mAbs in soluble phase induces a hyporesponsiveness following subsequent restimulation by iOKT3 in the absence of CD4 mAbs. This hyporesponsiveness was not associated with increased cell death during priming or restimulation cultures and could be reversed by the combination of phorbol ester + ionomycin, demonstrating a functional blockade of viable cells by CD4 mAbs. Following iOKT3 restimulation, hyporesponsive cells showed a lack of blast transformation and CD25 expression and were not able to respond to IL-2 since addition of high doses of exogenous IL-2 +/- CD28 mAbs did not reverse the hyporesponsiveness. However, costimulation with CD45RA mAb completely reversed the hyporesponsiveness, suggesting that CD45 controlled the CD4-mediated hyporesponsiveness.
Robinet
E
E
Laboratory of Immunology, INSERM U80 UCBL, Hôpital E. Herriot, Lyon, France.
Fournel
S
S
Fatmi
A
A
Revillard
J P
JP
D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000502:physiology*; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000276:immunology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007376:Interleukin-2; D016853:Muromonab-CD3; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D017493:Leukocyte Common Antigens