T-cell anergy induced by clonotype-specific antibodies: modulation of an autoreactive human T-cell clone in vitro.
Monoclonal antibodies (mAb) specific for the clonotype of an autoreactive T cell may be useful reagents in the modulation of autoimmune disease. We have previously reported the generation of a set of mAb specific for the clonotypic structure of a human T-cell clone recognizing an epitope of human cartilage gp-39. This glycoprotein was recently identified as a candidate autoantigen in rheumatoid arthritis. Here, we demonstrate for the first time that small amounts of immobilized anticlonotype mAb can induce anergy in the autoreactive clone. Following the anergic stimulus, T cells failed to proliferate upon restimulation as a result of a lack of interleukin-2 (IL-2) gene transcription. In addition, a diminished interferon-gamma (IFN-gamma) production was found. Our data indicate that anergy was not a result of T-cell receptor (TCR) downmodulation or the absence of free TCR. The anergic state was induced independent of costimulation or the presence of IL-2 and no protein synthesis was required for the induction of anergy. Anticlonotype mAb-induced anergy was prevented by cyclosporin A, suggesting that active signalling via the calcium/calcineurin pathway was required for the induction of anergy. In coculture experiments, anergic T cells were found to suppress the response of reactive cells from the same clone. This bystander suppression led to 90% inhibition of peptide-induced proliferation. Together, these findings suggest that mAb to the clonotypic structure of autoreactive T cells may be suitable reagents for the functional inactivation of these T cells in autoimmune diseases.
Steenbakkers
P G
PG
Department of Immunology, N. V. Organon, Oss, The Netherlands.
Boots
A M
AM
Rijnders
A W
AW
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000276:immunology; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D016572:Cyclosporine; D003513:Cycloheximide