We investigated relationships among chimeric TCR (cTCR) expression density, target Ag density, and cTCR triggering to predict lysis of target cells by cTCR+ CD8+ T human cells as a function of Ag density. Triggering of cTCR and canonical TCR by Ag could be quantified by the same mathematical equation, but cTCR represented a special case in which serial triggering was abrogated. The magnitude of target lysis could be predicted as a function of cTCR triggering, and the predicted minimum cTCR density required for maximal target lysis by CD20-specific cTCR was experimentally tested. cTCR density below∼ 20,000 cTCR/cell impaired target lysis, but increasing cTCR expression above this density did not improve target lysis or Ag sensitivity. cTCR downmodulation to densities below this critical minimum by interaction with Ag-expressing targets limited the sequential lysis of targets in a manner that could be predicted based on the number of cTCRs remaining. In contrast, acute inhibition of lysis of primary, intended targets (eg, leukemic B cells) due to the presence of an excess of secondary targets (eg, normal B cells) was dependent on the Ag density of the secondary target but occurred at Ag densities insufficient to promote significant cTCR downmodulation, suggesting a role for functional exhaustion rather than insufficient cTCR density. This suggests increasing cTCR density above a critical threshold may enhance sequential lysis of intended targets in isolation, but will not overcome the functional exhaustion of cTCR+ T cells encountered in the presence of secondary targets with high Ag density.