Myelin proteolipid protein-induced Th1 and Th2 clones express TCR with similar fine specificity for peptide and CDR3 homology despite diverse V beta usage.

Myelin-specific T-helper (Th) cells which induce encephalomyelitis belong to the inflammatory Th1 subset. Th2 cells recognizing similar epitopes potentially represent specific inhibitors of encephalitogenic Th1 cells. Since the differential stimulation of antigen-specific Th2 cells may be important in the regulation of autoimmune inflammatory disorders, we have examined the fine specificity of a Th1 and a Th2 clone, induced by immunization of SJL mice with native proteolipid protein (PLP) and specific for the PLP 139-151 sequence. Stimulation of the clones by synthetic peptides containing single alanine substitutions demonstrated that L141, W144, H147, and P148 represent critical residues. Surprisingly, this pattern was identical for both subsets. Competition studies indicated indirectly that L141 and P148 may be MHC-binding residues, whereas W144 and H147 contact the TCR. Sequencing of the TCR expressed by both Th subset clones demonstrated different V beta usage as well as variation in the D-region sequence and length. Interestingly, realignment of the sequence of the CDR3 regions showed striking homology. This study demonstrates that Th1 and Th2 subsets can express very similar peptide specificities, while utilizing very different TCR V beta chains. These results suggest that the therapeutic modalities based on either peptide antagonists or antibodies specific for CDR3 may have limited effectiveness in treating autoimmune disorders, since they may also target the beneficial arm of the immune response.