To study the biological consequences of cytokine production and apoptosis by intraepithelial lymphocytes (IEL), we have studied these characteristics in both the high and low density CD3+ IEL populations. Stimulation of low- or high-density CD3+ IEL via the T cell receptor (TCR)-CD3 complex using monoclonal anti-CD3, anti-alpha beta TCR or anti-gamma delta TCR antibodies resulted in opposing effects. In one case, a significant number of the high-density CD3+ T cells entered cell cycle from the resting stage (DNA replication was observed) and anti-TCR-CD3 treatment enhanced the numbers of interferon-gamma and interleukin-5 spot-forming cells in this cell fraction. In contrast, when the low-density alpha beta TCR+ or gamma delta TCR+ T cells were activated via the TCR-CD3 complex, DNA fragmentation was observed. These results demonstrated that the activation signals transduced via the TCR-CD3 complex resulted in their entry into the cell cycle and subsequent interferon-gamma and interleukin-5 production in the high-density IEL T cell subset. However, identical signals induced apoptosis in the majority of the low-density fraction of CD3+ IEL.