Abstract
Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.
Highlights
Introduction CutaneousT-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin T-cell lymphomas with primary involvement of the skin
The staphylococcal enterotoxins (SE)-positive supernatant induced a profound upregulation of FOXP3 and CD25 expression by malignant cells cocultured with nonmalignant cells (Fig. 1a, lower, middle)
SEA induced strong CD25 expression, but only weak FOXP3 expression when co-cultured with malignant cells (Fig. 1c, lower right), whereas nonmalignant cells in monoculture responded to SEA with a moderate upregulation of FOXP3, when compared to cultures without SEA (Fig. 1c, lower middle and left)
Summary
T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin T-cell lymphomas with primary involvement of the skin. A defining feature of SS is that advanced disease is associated with a distinctive tumor microenvironment dominated by TH2 cytokines[2,12] and a general absence of TH1 cytokines, such as IFN-γ and IL-12 Berger et al reported that immature dendritic cells in vitro induced a regulatory phenotype in malignant cells with expression of the IL-2 receptor subunit alpha (CD25) and FOXP3 This observation made the authors hypothesize that CTCL involved malignant proliferation of regulatory T (Treg)
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