Tumor Immunity by Hydrophobic Bearing Antigens.

摘要

CD8+ cells expressing high numbers of TCR per cell (TCRhi) are important mediators of anti-tumor effects. To understand the relationship between TCR density and Ag affinity for TCR in the outcome of differentiation of CTL recognizing tumor Ag, we analyzed perforin induction in ovarian tumor- associated lymphocytes in response to the smallest possible changes in the atomic forces of interaction between Ag and TCR. Stimulating undifferentiated, apoptosis-resistant CD8+ cells expressing high levels of E75-TCR (TCRhi) with variants of the CTL epitope E75, HER-2 (369-377), induced their stepwise differentiation, first to IFN-gamma+ Perf-, and then to TCRhi IFN-gamma+ Perf+ cells. Blocking caspase-9 activation at Ag stimulation also enhanced the generation of TCRhi Perf+ cells, demonstrating that TCR density dictated the pathway of death activated by stimulation with the same agonist. Expansion and differentiation of TCRhi Perf+ CTL required an agonist of optimal CH2 side chain length. Side chains one CH2 shorter or longer than optimal were either less stimulatory or induced death of TCRhi Perf+ cells. Differentation of TCRhi CD8+ cells can be finely tuned by side chains which induce small increments in the affinity of the Ag for TCR below the affinity which induce apoptosis.