Counter-regulation of cytolytic activity and cytokine production in HIV-1-specific murine CD8+ cytotoxic T lymphocytes by free antigenic peptide.

We have reported previously that the cytolytic activity of murine CD8(+) cytotoxic T lymphocytes (CTL) specific for HIV-1 gp160 envelope glycoprotein was markedly inhibited by brief exposure to the free minimal antigenic peptide (I-10: 10mer peptide from gp160) by direct binding to class I MHC molecules of specific CTL in the absence of antigen-presenting cells (APC). Here, we show that treatment of such CTL with the peptide induced not only the inhibition of cytolytic activity but also IL-2Rbeta down-modulation, followed by the inhibition of IL-2-dependent growth. The peptide-mediated inhibition and restoration of expression of IL-2Rbeta were well correlated with changes in both cytolytic activity and IL-2-dependent growth of the CTL. Since enzymatic activity of granzyme B, and mRNA expression of granzyme B and perforin were significantly reduced in peptide-treated CTL, the inhibition of cytolytic activity was mainly caused by the exhaustion of cytolytic molecules. Moreover, treatment of the CTL with the epitopic peptide resulted in production of high levels of IL-2, IFN-gamma, tumor necrosis factor-alpha and MIP-1beta in the culture supernatant. Maximum amounts of cytokines were obtained in the culture supernatant when the level of cytolytic activity was the lowest. Thus, although the CTL temporarily lost their cytolytic activities, they simultaneously gained the abilities to produce cytokines for activation of various cell populations. These changes induced by free antigenic peptide in CD8(+) CTL reveal an interesting counter-regulation between their cytolytic activities and cytokine production.