Peripheral blood mononuclear cells (PBMC) from an HLA DRw6/7 individual were stimulated with tetanus toxoid (TT). T cell blasts were cloned by the limiting dilution technique in the presence of TT and irradiated autologous PBMC (iPBMC). Twelve were propagated under interleukin 2 and restimulated weekly with TT and iPBMC. All proliferated specifically in response to TT or either the alpha or beta chain of the toxin molecule. HLA restriction of specific proliferative responses was analyzed using a panel of HLA-typed unrelated donors and selected families, and blocking experiments with anti-HLA class I and class II monoclonal antibodies (mAb). Three types of restriction were observed: (a) autologous restriction; the inhibition observed using anti-HLA DR mAb as well as family studies performed previously with a similarly restricted clone obtained from the same donor suggest an HLA DRw6-linked restriction; (b) an HLA DR7 restriction was found for 2 clones, specific for alpha or beta chain; the identical pattern of inhibition obtained with two different mAb belonging to the same cluster suggests that these clones may be restricted by the same (or a very close) epitope of the HLA DR7 molecule; (c) an unusual restriction pattern was found for one clone; PBMC from more than 80% of donors could present TT whatever their degree of HLA compatibility with the autologous donor. Family studies were unable to disclose any restriction with known class II (or class I) antigens. While no inhibition was observed with anti-DR or -DC reagents, a mAb that recognizes class I antigen when associated with beta 2-microglobulin did inhibit the proliferation of this clone.