Sjogren’s syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Recent studies (1) on T cell receptors (TCR), using polymerase chain reaction and sequencing methods, have shown that certain T cells in inflamed lesions expand clonally, suggesting antigen-driven stimulation. What arc the autoantigens recognized by autoreactive T cells in inflamed lesions of SS patients? We recently reported evidence that 52-kd Ro/SS-A might act as an autoantigen for autoreactive T cells in these glands, and we identified the T cell epitope DEREQLRILG at position AA203-212 of the RolSS-A protein, using synthetic amino acids and cell proliferative analysis (23).’The present study was undertaken to characterize other T cell epitopes recognized by T cells infiltrating the labial salivary glands of patients with SS. Synthetic peptide combinatorial libraries were used as candidate autoantigens. Peripheral blood lymphocytes from patients with SS were cultured with 400 groups of synthetic amino acid libraries, and T cells bearing a TCR identical to that in T cells infiltrating the labial salivary glands were then examined by the single-strand conformational polymorphism (SSCP) method (4). The results in Figure 1A show that peptides encoding an xxxVxxxxRxxx motif constituted a 1’cell epitope in SS patients with HLA-DRBl” 1101. A computer analysis of the combination of the xxxVxxxxRxxx motif and DRBl” ll01-binding amino acid motifs such as WxxMxRxxx (5) showed that WAEILRIGRV (TCRBV6S7) and WVNMLRRGI (Staphylococcus uureus heat-shock protein 10160 [hsp10/69]) were suitable candidates for antigens (Table 1). These same 2 synthetic amino acidreactive T cells were found in labial salivary glands by SSCP analysis (Figure 1B). TCRBV6S7-reactive T cells produced both interleukin-2 (IL-2) and IL-4, while hsp10160-reactive T cells produced only IL-2 in vitro (Figure 1C and Table 1). Our results provide evidence that S aureus hspl0160 and human TCRBV6S7 are additional antigens recognized by T cells infiltrating the labial salivary glands of patients with SS. The WVNMLRRGI segment (position 482-490) of the hsp10160 gene from S aureus showed 67% homology with the xVNMVxxGT fragment (position 5 10-518) of human chaperonin (hsp60). This suggests that hsp10160 derived from S aureus may act as an antigen to activate T cells and that these cells cross-rcact with the homologous human hsp60 autoantigen. Further examination of the T cell response to human hsp60 will be necessary to prove a molecular mimicry mechanism in the generation of autoimmunity. In contrast, the VDJ junctional amino acid of the TCRBV6S7 gene was able to induce TCRBV6-positive T cells and to produce IL-4 as well as 1L-2. This indicates that the variable region of TCR might act as an idiotypic determinant for autoreactive T cells and as a regulatory T cell epitope on autoantigens. In conclusion, these findings demonstrate the presence of regulatory T cell epitopes on autoantigens as well as autoaggressive T cell epitopes in inflamed lesions in SS. We thcrefore propose that vaccination with synthetic peptides of regulatory T cell epitopes that induce regulatory T cells, and with analog peptides of autoaggressive T cell epitopes that undergo anergy, might be useful as a new stratcgy for specific treatment of SS.