Virus-specific CTL play a major role in early antiviral protection against lymphocytic choriomeningitis virus (LCMV). When mice are infected with high doses of certain LCMV isolates, the initiated CTL response may vanish before the virus is eliminated completely. To evaluate the possibility that this may be because of CTL lysing CTL, we studied the susceptibility to lysis of LCMV-specific CTL clones and of primary immune spleen cells in vitro and in vivo. Confirming earlier reports, CTL were lysed in vitro when incubated with their specific Ag peptide; lysis was MHC restricted because T cell clones derived from allogeneic bone marrow chimeras that do not express the correct restriction element were not susceptible to mutual CTL lysis. The density of CTL cultures correlated with the degree of inactivation of CTL, indicating that CTL lysed each other mutually rather than committed suicide. To assess CTL-mediated lysis of CTL in vivo, mice were infected s.c. into the footpad with LCMV, and shortly before the CTL-dependent footpad swelling developed by day 6 to 7, specific peptide was injected locally. The regional lymph node (LN) was reduced in size, contained about 10 times fewer cells, and only 2% to 3% of the lytic activity when compared with several control LN. This drastic local effect was observed within a few hours and was accompanied by DNA fragmentation. Thus, in this model system, peptide loading of lymph node cells may lead to CTL-mediated cytotoxicity and death of T cells (including CD8+ effector cells and other LN cells) in vivo. These results may suggest that, during overwhelming virus infections, lysis of CTL passively loaded with relevant released peptides possibly may contribute to the impairment of immune responses.