Genetic control of immune response was investigated by family and population analyses in humans. It was first recognized that there are high responders and low or non responders to natural antigens in human population. Family analysis revealed that low responsiveness to streptococcal cell wall antigen (SCW) was inherited as an HLA-linked dominant trait. CD8+ suppressor T cells existed in low responders and depletion of the CD8+ T cells from low responders could restore the strong immune response to SCW. Therefore the gene controlling the low response to SCW was designated as an immune suppression gene for SCW. Immune suppression gene for SCW was in strong linkage disequilibrium with particular alleles of HLA-DQ locus. The association between HLA-DQ alleles and low responsiveness mediated by CD8+ suppressor T cell was also observed for schistosomal antigen, Mycobacterium leprae antigen, tetanus toxoid, cryptomeria pollen antigen and hepatitis B virus surface antigen suggesting that low responsiveness to those antigens was also controlled by immune suppression genes. Anti-HLA-DR monoclonal antibodies inhibited the immune response to those antigens of high responders in vitro, but anti-HLA-DQ monoclonal antibodies did not. On the other hand, anti-HLA-DQ monoclonal antibodies restored the immune response in low responders. Therefore, it is suggested that HLA-DR upregulates immune response and that HLA-DQ downregulates it and that HLA-DQ is epistatic to HLA-DR in the regulation of immune response in humans. Furthermore, direct evidence for the differential in immune regulation between HLA-DR and DQ was obtained by analyzing the SCW specific T cell lines from low responders. SCW specific and HLA-DQ restricted CD4+ T cell lines could activate CD8+ suppressor T cells which in turn downregulate SCW specific CD4+ T cells whereas SCW specific and HLA-DR restricted CD4+ T cell lines could not activate CD8+ suppressor T cells. All these observation clearly demonstrated that the HLA-linked immune suppression genes exist in humans to control low response to natural antigens.