The Epstein-Barr virus (EBV) transformed lymphoblastoid cell line (LCL-721) and some of its HLA loss mutant derivatives were used to study the immune specificity of the autologous proliferative T cell response to antigens expressed as a result of EBV infection. We have measured secondary and tertiary proliferative responses to well-characterized variants that lack expression of some or all known class II gene products (DR, DQ, and DP). These experiments prove that the region mapping between DR/DQ and glyoxalase I (GLO) of one haplotype controls at least one specific restriction element which is recognized in the autologous response to LCL-721. Furthermore, specific proliferative responses to variants lacking expression of all known class II gene products indicate the recognition of determinants other than DR, DQ, and DP.