We studied the activation of small resting mouse T lymphocytes by antibodies to the T cell antigen receptor in combination with antibodies to other T cell surface antigens. Solid-phase but not soluble antibodies KJ16-133 and F23.1, both directed to beta chains of the V beta 8 family, activate T cells to proliferate in the presence of growth factors, in a dose-dependent fashion. Antibodies to Lyt-2 and to L3T4 had no activating effect at any concentration. However, submitogenic concentrations of KJ16-133 and of F23.1 synergized with a wide range of concentrations of anti-Lyt-2 and anti-L3T4 to cause T cell proliferation similar or greater in magnitude to that caused by high concentrations of anti-T cell receptor antibody. Synergistic activation was also observed with antibodies to Lyt-1, LFA-1 and H-2 class I antigens but to a significantly lower degree. This was particularly clear in limiting dilution experiments in which the corrected frequencies of T cells proliferating in response to low amounts of anti-T cell receptor antibody together with anti-Lyt-2 were 1/4 to 1/7 for BALB/c T cells. The frequencies of BALB/c T cells responding to high concentrations of anti-T cell receptor antibody alone were between 1/14 and 1/126 and still lower frequencies of T cells proliferated in synergistic responses with anti-LFA-1 or anti-Lyt-1. Synergistic activation leads to the induction of functional cytotoxic cells. We interpret these data as suggestive that cross-linking of the T cell antigen receptor with either Lyt-2 (CD8) or L3T4 (CD4) represents an optimal activating signal for resting T cells. We think that, in physiological T cell activation, cross-linking of the T cell receptor to CD8 or CD4 is induced by their simultaneous binding to major histocompatibility complex (MHC) class I (for CD8) or MHC class II (for CD4) molecules on stimulator cells. We consider the possibility that similar cross-linking requirements may also exist during T cell repertoire selection in ontogeny, thus accounting for the strict coexpression of MHC class I and class II-restricted T cell receptors with CD8 and CD4 molecules, respectively.