SUMMARYThere are two lypes, A and B, of Epstein-Barr virus (EBV) and B95-8 represents the common lype A laboratory strain. Herein, we show in a family study thai paternal EBV-specific cyiotoxie T lymphocytes (CTL) generated in short-term cultures following stimulation with the autologous B95-8-lransformed lymphoblastoid cell line (LCL) or B cells freshly infected wilh the B95-8 isolate did not Iyse haptoidentiati B95-8 LCL expressing the HLA-AL -B8. -DR3 paternal haplotype. In contrast, the haploiUentical B95-8 LCL expressing the HLA-Al I, -B5i, -DR? paternal haplotype was sirongly lysed. Moreover, paternal CTL generated in response lo stimulation with the B95-8 LCL expressing the haploidentical HLA-Al. -B8, -DR3 paternal haplotype included an allogeneic response against the maternal haplotype but no EBV-specific response as shown by the poor lysis ofthe autologous LCL target cells. However, stimulation with the hapioidentieal HLA-Al I. -B51. -DR7 paternal haplotype resulted in the generation of both an allogeneic and an EBV-specific response. CTL clones were generated from two HLA-B8' donors in response to stimulation wilh the aulologous type A LCL transformed wiih wildlype EBV. The clones were cross-reactive for an immunodominant B95-8-associalcd peplide epitope ihat interacted with the HLA-B8 allcie but failed to Iyse B95-8-transfomied LCL largets unless the targets were prc-coated with ihe exogenous peptide. A CTL clone that was inilially stimulated wilh the autologous BL74 LCL lysed the spontaneous autologous LCL and spontaneous LCL from an HLA-B8 * donor, but failed to Iyse the B95-8 LCL from that donor. The observed haplotype preference can be explained in terms of sequence variation between the B95-8 and the corresponding wildlype epitope. Our findings may help lo clarify the role of EBV in the pathogenesis of primary Sjogren's syndrome which is closely associated with HLA-B8.