Autoreactive responses to an environmental factor. 2. Phthalate-induced anti-DNA specificity is downregulated by autoreactive cytotoxic T cells.
An environmental factor (phthalate) was shown, in our previous study, to induce serum anti-DNA responses in BALB/c, NZB and lupus-prone NZB/W F1 mice. Out of such anti-phthalate responses, cross-reactive populations were identified that strongly bind phthalate, DNA, or both. A phthalate-specific BALB/c monoclonal antibody, 2C3-Ig (gamma1,kappa), showed considerable affinity for DNA and had extensive sequence homology with the heavy and light chain variable regions of a known anti-DNA immunoglobulin, BV04-01, from lupus-prone NZB/W F1 mice. This study was initiated to address how BALB/c mice, but not NZB/W F1 mice, are protected from these adverse autoreactive B cells. Using 2C3 hybridoma cells as the prototype autoreactive BALB/c B cell, we determined whether its DNA-binding monoclonal antibody would induce any regulatory cell-mediated immune responses. Synthetic idiopeptides corresponding to the heavy and light chain variable regions of 2C3-Ig were found to be effective at inducing specific effector cells in BALB/c mice, but not in lupus-prone F1 mice. The splenocytes from BALB/c mice incubated in vitro with the idiopeptides, particularly the complementarity-determining region 1 (VL1) of the 2C3-Ig light chain, showed significant proliferative and cytolytic responses. A CD8+ cytotoxic T-lymphocyte (CTL) response was elicited that recognized the VL1 peptide presented by the Kd allele, and affected the growth of 2C3 cells. In vivo depletion of CD8+ T cells in BALB/c mice significantly decreased this CTL activity but increased the anti-DNA humoral response. These results suggest that autoreactive CTLs are induced in non-autoimmune prone mice as a mechanism to downregulate self-reactive B cells.