Cross-linking CD4 molecules with the use of specific mAbs induced Ag-nonspecific, MHC-unrestricted killing by human or bovine CD4+ T cells and human allospecific T cell clones against virally infected (bovine herpesvirus-1 and herpes simplex virus-1) target cells. Heat-aggregated goat IgG anti-mouse IgG elevated CD4 cross-linking efficiency, resulting in augmented killing activity by effector cells. However, Ab-activated effector cells failed to kill tumor target cell lines, e.g., K562, Daudi (human), and BL3 (bovine). The result supports the hypotheses that the CD4 molecule plays an important role in activating CD4 cytotoxic cells and that viral glycoproteins participate in conjugating target cells with activated effector cells in two species. The herpesviruses eliciting killing represent potential natural infections for each species. The relationship between a cytolytic response and cell proliferation was independent because cross-linking of CD4 molecules induced cytotoxicity but not T cell proliferation, in contrast to cross-linking CD3 molecules. Our findings of non-MHC-restricted cytotoxic lymphocytes induced by cross-linking CD4 molecules identify an activation mechanism of antiviral cytotoxicity.

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