Activation of murine cytotoxic cells with interelukin-2 and the bacterial superantigen staphylococcal entertoxin A.

Abstract

Natural killer (NK) cells and T lymphocytes are the major effector cells that can recognize and kill tumor cells. NK cells have a constitutive cytotoxic activity and kill a wide spectrum of tumor cells while T cells recognize specific tumor antigens and need to be activated through their TCR to differentiate into cytotoxic T lymphocyte (CTL) killers or T helper cells. Interleukin-2 is the principal growth factor for both NK and T cells. Both in vitro and in vivo stimulation with IL-2 and the superantigen, Staphylococcal enterotoxin A (SEA) were used to characterize murine cytotoxic cells functionally and phenotypically. Culturing of lymphoid cells with IL-2 preferentially expanded NK cells and induced lymphokine activated killer (LAK) activity that preferentially was mediated by IL-2 activated NK cells (NK-LAK) and only to a minor extent by T cells (T-LAK). Stimulation of lymphoid cells with SEA preferentially expanded T cells expressing certain TCR variable beta elements both in in vitro culture and in vivo following intraperitoneal (i.p.) injections of SEA. T cells responded with induction of profound cytokine production and cytotoxic activity that could be targeted to tumor cells expressing MHC class II, this is termed staphylococcal enterotoxin dependent cell-mediated cytotoxicity (SDCC). However, SEA induced effects are transient and anergy and deletion eventually develop which lead to reduced endogenous IL-2 production and CTL activity. We could show that continuous IL-2/IL-2R stimulation through i.p. injections of rIL-2 twice a day had multiple effects on SEA induced T cell activity. Exogenous IL-2 increased T cell expansion and superinduced as well as prolonged CTL activity. Exogenous IL-2 also prevented SEA induced down-regulation of cytotoxic activity and cytokine production with maintained high levels of SDCC and endogenous IL-2 production. Combined treatment with SEA and IL-2 further superinduced cytokine production. Collectively, these data support that administration of continuous IL-2/IL-2R stimulation might be advantageous for SEA based tumor therapy