Autoreactive responses to an environmental factor. 2. Phthalate‐induced anti‐DNA specificity is downregulated by autoreactive cytotoxic T cells

Summary 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 (γ1,κ), 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 K d 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.