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Down-modulation of CD3ζ expression on CD8 T lymphocytes occurs, independently of other T-cell receptor (TCR)-CD3 components, in tumor-infiltrating lymphocytes, human immunodeficiency virus infection, and autoimmune disease. These associations suggest that it might be related to chronic antigenic stimulation. CD3ζ down-modulation was found, however, in CD8 T cells that proliferate in response to acute viral infections. In 3 otherwise healthy donors with acute gastroenteritis, infectious mononucleosis, and Epstein–Barr virus/cytomegalovirus/mononucleosis, 30% to 60% of circulating CD8 T cells had down-modulated CD3ζ to below the level of detection. The CD3ζ-T cells were also CD28− but expressed the activation markers HLA-DR and CD57. CD3ζ–CD28– T cells are effector CTL because they express perforin and produce IFN-γ, but not IL-2, on activation and contain the viral-specific cytotoxic T lymphocyte (CTL). However, CD3ζ–CD28–T cells generally do not express CD25 after anti-CD3 and anti-CD28 stimulation and are not cytotoxic until they are cultured with IL-2 overnight. Cytotoxicity coincides with the re-expression of CD3ζ but not CD28. Down-modulation of CD3ζ and CD28 on effector CTL may control CTL triggering and proliferation to prevent immunopathogenesis.