Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes

• Published in: The Journal of immunology (1950) Vol. 151; no. 5; pp. 2444 - 2452
• Main Authors: Mehrotra, PT, Wu, D, Crim, JA, Mostowski, HS, Siegel, JP
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Assoc Immnol 01.09.1993; American Association of Immunologists
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; CD8 Antigens - analysis; Cells, Cultured; Cytotoxicity, Immunologic - drug effects; Drug Synergism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Interleukin-12; Interleukin-2 - pharmacology; Interleukin-4 - pharmacology; Interleukins - pharmacology; Lymphocyte Activation - drug effects; Lymphokines, interleukins ( function, expression); Recombinant Proteins - pharmacology; Regulatory factors and their cellular receptors; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Human; Immunostimulation; Cytokine; T-Lymphocyte; Cytotoxicity; Interleukin 12; Immune regulation; Cell subpopulation; Biological activity
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.151.5.2444

We have studied the effects of human rIL-12 on the proliferation and generation of cytotoxic activity in human CTL precursors. Purified human blood CD8+ T lymphocytes were stimulated overnight with immobilized alpha-CD3 and cultured 3 to 4 additional days under various conditions. The addition of IL-12 resulted in a marked (10- to 20-fold), dose-dependent, augmentation of cytotoxicity per cell with a smaller (2-fold) increase in cell number. IL-12 augmentation of proliferation and cytotoxicity of CD8+ T cells was not inhibited by a mAb to the p55 subunit of the IL-2 receptor (alpha-Tac) at a concentration sufficient to block the activity of exogenously added IL-2, indicating that the activity of IL-12 did not require IL-2. Addition of IL-12 at the time of alpha-CD3 activation or 1 day later was highly effective at augmenting cytotoxicity, whereas delayed addition of IL-12 (day 2 or 3) resulted in a smaller increase in CTL activity with no increase in cell number. IL-12 at all doses tested synergized with low dose IL-2 in inducing the proliferation and differentiation of CD8+ T cells. The synergistic effect was not blocked by adding neutralizing serum to IFN-gamma. In contrast to this synergistic effect, IL-12 significantly inhibited the proliferation observed in the presence of higher concentrations of IL-2 (4,500 and 13,500 pg/ml). An inhibitory effect of IL-12 was also observed when IL-12 was added to CD8+ T lymphocytes 3 days subsequent to activation with alpha-CD3 and IL-2. This broad set of potent effects of IL-12 on CD8+ T cell responses suggests that IL-12 may play an important immunoregulatory role on CTL development in vivo and may be a useful tool for manipulating this process in vivo for investigational and immunotherapeutic purposes.