T‐cell anergy induced by clonotype‐specific antibodies: modulation of an autoreactive human T‐cell clone in vitro

Abstract

SUMMARYMonoclonal 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-c (IFN-c) 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 mAbinduced 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.

Vaccination with Single Chain Antigen Receptors for Islet-Derived Peptides Presented on I-Ag7 Delays Diabetes in NOD Mice by Inducing Anergy in Self-Reactive T-Cells

“…Anergy induction by anti-clonotypic antibodies in mouse and human T-cells has been studied in vitro for some time [44]; [45] and some features reported in those studies are consistent with those observed here, including the suppression of antigen-induced cytokine release, the lack of down-regulation of the targeted TCR, or loss of T-cells due to cell death or apoptosis. However, the non-responsiveness of anergic BDC2.5 T-cells to exogenous IL-2 and their inability to mediate suppression of normal BDC2.5 T-cells are features, which differ from those found in the earlier studies.…”

Reversibility with Interleukin-2 Suggests that T Cell Anergy Contributes to Donor-Specific Hyporesponsiveness in Renal Transplant Patients

“…Second, it has been suggested that there are different levels of T cell unresponsiveness that are associated with different degrees of reversibility (16). Finally, it has been reported that cyclosporin may prevent the induction of anergy (17,18). However, the effect of cyclosporin on anergy induction is far from clear; many studies have reported the induction of anergy in the presence of cyclosporin (19 -23).…”