Help signals provided by lymphokines modulate the activation and apoptotic programs induced by partially agonistic peptides in specific cytotoxic T lymphocytes.

Inefficient recognition of altered peptide ligands (APL) by specific CTL is believed to contribute to the failure of immune control over tumors and progressive viral infections. A link between deficient help signals and the appearance of CTL epitope mutants has been suggested by recent studies. However, the regulation of APL activity by immunologic help is not well understood. We analyzed the capacity of exogenous IL-2 and IL-15, which are physiologically produced by cells of the adaptive and innate immune system, respectively, to modulate proliferation, responsiveness to repeated stimulation and apoptotic programs triggered in specific CTL by either fully or partially agonistic peptide ligands. We show that signals induced by the lymphokines synergize with weak TCR signaling induced by partially agonistic APL, converting many of these peptides from inhibitory to stimulatory ligands. Some APL partially suppress the responsiveness of specific CTL to secondary stimulation, while this inhibitory effect is diminished if APL-stimulated cells are cultured in the presence of either of the lymphokines. We also demonstrate that IL-2 and IL-15 suppress up-regulation of the Bcl-2 family member Bim and induction of a death receptor-independent apoptotic program triggered by partially agonistic APL. Our results suggest that under conditions of insufficient immunologic help, partially agonistic APL may actively suppress specific CTL responses and become especially advantageous for immune escape of tumors or viruses.