Effects of natural killer cell stimulatory factor on human lymphocytes

Susan H Chan, University of Pennsylvania


Evidence suggests that soluble mediators produced by activated lymphocytes, known as lymphokines, are critical to the immune response. When lymphocytes are activated by antigen or by virus infection, they secrete lymphokines and perform effector functions such as immunoglobulin production by B cells, cell-mediated cytotoxicity by T cells, and spontaneous as well as antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells. The mechanisms by which lymphokines regulate lymphocyte activation and proliferation are unclear. However, lymphokines have been shown to regulate the expression of their own receptors, induce the secretion of additional cytokines, and stimulate lymphocyte proliferation. We have examined these mechanisms using a novel cytokine, NK cell stimulatory factor (NKSF), purified in our laboratory from the conditioned medium of an Epstein-Barr virus-transformed B lymphoblastoid cell line. NKSF is a 70 kilodalton (kD) heterodimer that is composed of a 35 and 40 kD chain. NKSF induces interferon-gamma (IFN-$\gamma$) production from human peripheral blood lymphocytes, augments cytotoxicity of NK cells, and enhances T cell proliferation in response to lectins and phorbol diesters. In this study, I have demonstrated that NKSF induces IFN-$\gamma$ production from peripheral blood T and NK cells with a mechanism that is resistant to immunosuppressive drugs, and synergizes with other IFN-$\gamma$ inducers in this activity. The mechanism by which NKSF regulates IFN-$\gamma$ production occurs at multiple levels. NKSF induces IFN-$\gamma$ expression at the level of gene transcription. In addition, NKSF synergizes with interleukin 2 at the level of IFN-$\gamma$ mRNA stability. By contrast, the synergy between NKSF and phorbol diester is due to regulation at the transcriptional level by both inducers and at the post-transcriptional level by phorbol diester alone. Furthermore, I have demonstrated that NKSF acts as a powerful progression factor for cultured lymphocyte proliferation in concentrations of less than 1 picomolar. The potent biological activities of NKSF on both T and NK cells, and the ability of B cells, at least after virus infection, to produce this lymphokine, suggest that NKSF might play an important role in regulating the immune response. The ability of virus-transformed B cells to produce NKSF may suggest a role for this lymphokine in resistance against infection or malignancy. Moreover, the unusual heterodimeric structure of NKSF identifies it as a new type of cytokine with potential novel mechanisms for ligand-receptor interaction.

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Recommended Citation

Chan, Susan H, "Effects of natural killer cell stimulatory factor on human lymphocytes" (1991). Dissertations available from ProQuest. AAI9125610.