Bacterial antigen fragments complexed with class II major histocompatibility molecules (HLA-D) on antigen presenting cells (APCs) stimulate CD4+ T lymphocyte proliferation, presumably to protect the host. This study examined these responses to antigens of two periodontal pathogens in four groups (n = 15) of age- (young adult) and sex-matched Caucasian subjects with or without type 1 diabetes and moderate to severe periodontitis: Group DP = diabetics with periodontitis; Group DnP = diabetics without periodontitis; Group nDP = nondiabetics with periodontitis; and Group nDnP = nondiabetics without periodontitis. HLA-D phenotypes for each subject were determined by lymphocytotoxicity assays. T lymphocytes purified from peripheral blood were stimulated in cell culture with APC pulsed with various concentrations of tetanus toxoid, Porphyromonas gingivalis, and Capnocytophaga sputigena antigens. T lymphocyte reactivity (3H thymidine incorporation) was numerically lower in cultures from diabetics stimulated with unpulsed APC (not significant), and antigen-pulsed cultures showed low proliferation and no significant differences among groups. Stimulation indices in cultures from diabetic patients stimulated with P. gingivalis or C. sputigena, however, were significantly elevated at all antigen concentrations compared to nondiabetic cultures. The occurrence of HLA-DR4 was moderately associated with diabetes (P < 0.05) and highly associated with periodontitis (P < 0.001, log-linear model for categorical variables); and HLA-DR53 and HLA-DQ3 were significantly associated with periodontitis (P < or = 0.02). HLA-DR was crucial to lymphocyte stimulation (anti-HLA-DR blocking experiments), but the low peripheral blood T cell reactivity to antigens of periodontal pathogens could not be linked with HLA-D type or periodontitis susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)