Tumour-specific cytotoxic T lymphocyte activity in Th2-type Sézary syndrome: its enhancement by interferon-gamma (IFN-gamma) and IL-12 and fluctuations in association with disease activity.

Sézary syndrome (SzS) is the leukaemic variant of cutaneous T cell lymphoma (CTCL), whose malignant T cells are of the Th2 type in most cases. In this study we investigated the tumouricidal activity of cytotoxic T lymphocytes (CTL) present in peripheral blood of a patient with Th2-type SzS, focusing on the effect of IL-2, IFN-gamma and IL-12 on their cytotoxic activity, and the relationship between their lytic capacity and the patient's clinical course. At four different time points during a 2-month clinical period, CD4+CD7- Sézary cells and CD8+ cells were separated from the patient's circulating cells. CD8+ cells were cultured with chemically attenuated, purified Sézary cells in the presence of IL-2 to develop specific cytotoxicity. The CD8+ cells thus cultured exhibited lytic activity against autologous Sézary cells. Concomitant addition of IFN-gamma or IL-12 exerted a synergistic cytolytic effect with IL-2 on the tumour cells. Cytotoxicity inhibition studies using MoAbs revealed that the cytotoxicity operated in MHC class I-, CD8- and alphabeta T cell receptor-dependent manners. Furthermore, eight CD8+ T cell clones generated from cultured CD8+ cells exhibited a strong cytotoxicity against Sézary cells in an MHC class I-restricted fashion. During the clinical course, the activity of generated CTL and the number of CD8+ cells were inversely correlated with disease activity as assessed by the serum level of lactate dehydrogenase. These findings suggest that CTL down-regulate the growth of malignant T cells in this long-standing disease. Since Th2 cytokines such as IL-4 down-modulate CTL activity, CTL are assumed to be usually suppressed in SzS, whose malignant T cells are of Th2 type. It is likely that the administration of IFN-gamma normalizes this Th2-skewing state, activates CTL, and thus exerts the therapeutic effectiveness in the treatment of CTCL.