SummaryWe had previously obtained evidence that among normal subjects the humoral antibody response to hepatitis B surface antigen (HBsAg) was bimodally distributed with about 14% of subjects producing <1,000 estimated radioimmunoassay RIA units . From the study of major histocompatibility complex (MHC) markers in the very poor responders who produced <36 estimated RIA units of antibody, it appeared that there was an excess of homozygotes for two extended haplotypes [HLAB8, SC01, DR3] and FC31, DR7] . This finding suggested that a poor response was inherited as a recessive trait requiring nonresponse genes for HBsAg on both MHC haplotypes and was strengthened by finding a much lower antibody response among prospectively immunized homozygotes for [HLAB8, SCOT, DR3] compared with heterozygotes . In the present study, we have analyzed the cellular basis for nonresponse to this antigen by examining antigen-specific proliferation of T cells from responders and nonresponders in the presence and absence of autologous CD8+ (suppressor) cells .Peripheral blood cells from nonresponders to HB&Ag failed to undergo a proliferative response to recombinant HB&Ag in vitro, whereas cells from responders proliferated vigorously. This failure of cells from nonresponders to proliferate was not reversed in cell mixtures containing CD4+ and antigen-presenting cells devoid of CD8+ cells . There was no difference between responders and nonresponders with respect to the number of circulating T cells or their subsets, or the proliferative response to mitogens such as pokeweed or phytohemagglutinin or another antigen, tetanus toxoid.Our results indicate that our HBsAg nonresponding subjects have a very specific failure in antigen presentation or the stimulation of T helper cells, or both. Our evidence is against specific immune suppression as the basis for their nonresponsiveness. The failure of antigen presentation or T cell help is consistent with recessive inheritance of nonresponsiveness and suggests that response is dominantly inherited .T he humoral antibody response to protein antigens is controlled by class II MHC genes in the mouse and other mammalian species (1, 2) . Although antibody responses to synthetic peptides are controlled by MHC genes in mice, experiments to show this in humans are less conclusive (3-5) and the presence or absence of response has not been associated with any specific HLA haplotype. Other studies in vitro using human cells have provided evidence for MHC immune suppression genes to collagen (6), cryptomeria japonica pollen (7), schistosomal antigen (Sj)t (8), and streptococcal cell wall 'Abbreviations used in this paper HB, hepatitis B ; HB&Ag, hepatitis B surface antigen; ML, ncobacterium leprae antigen ; NBCS, newborn calf serum; SCW, streptococcal cell wall antigen; Sj, schistosomal antigen .