We present here the first report of a human helper/inducer T cell clone (F6) that specifically recognizes tetanus toxoid (TT) in the context of self-major histocompatibility complex (MHC) determinant(s) (HLA-DR3), and in addition recognizes a specific but unrelated MHC determinant(s) in the absence of conventional antigen. Extensive subcloning insured that the cells were progeny of a single cell. Furthermore, removal of the cells proliferating to the alloantigen with bromodeoxyuridine and light removed cells responding to both TT plus self-MHC and to the stimulating alloantigen, again indicating that F6 was the progeny of a single cell. The alloantigen recognized by this TT-specific clone appears to be closely linked to HLA-DR4 since cells from 13 of 14 HLA-DR4+ donors stimulated F6. An antiserum which recognizes HLA-DR4, when added to cultures, blocked the alloreactivity of F6, and in addition blocked its proliferation to TT plus HLA-DR3. Absorption of this antiserum with HLA-DR4+ cells or with TT-pulsed HLA-DR3+ cells removed its capacity to inhibit the proliferation of F6. These results suggest that the antigen recognition unit on F6 is stimulated both by allodeterminants expressed on HLA-DR4 cells and by TT plus HLA-DR3. These moieties cross-react at the T cell recognition level as well as at the antibody level.