Toxins fuel T cell lymphoma

Simplified schematic showing the proposed mechanism of how SEs may suppress cellular immunity and antitumor responses.

(A) In contrast to benign T cells, malignant T cells typically express a monoclonal TCR VΒ chain and often exhibit decreased expression or function of the TCR complex. SEs may therefore in many cases not stimulate malignant T cells directly but rather indirectly through activation of benign T cells.
(B) Upon colonization with enterotoxin-producing SA bacteria, SEs bind MHC-II molecules expressed on malignant T cells, benign T cells, and antigen-presenting cells. SEs bound to MHC-II molecules subsequently crosslink TCRs on benign T cells, which elicits cell-cell contact–dependent interactions between the benign and malignant T cells and triggers secretion of IL-2 from the benign T cells.
(C) These signals in turn induce high expression of IL-10 from the malignant T cells via a Jak3/Stat3- dependent pathway. IL-10 secreted from the malignant T cells can dampen cellular immunity by several means. For example, IL-10 impairs the maturation of dendritic cells, represses the expression of Th1 cytokines (interferon-γ, IL-12), inhibits T-cell activation, and pro- motes the function of regulatory T cells as well as the development of immunoregulatory M2 macrophages (MΦ), collectively contributing to suppression of cellular immunity and antitumor immune responses. The malig- nant T cells, however, display deficient expression of IL-10R and are therefore protected against the suppressive effects of IL-10. DC, dendritic cell; IFN-γ, interferon-γ.

Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with sig- nificant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. We have shown that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3-mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10.

Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. We can thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.

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Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma

Andreas Willerslev-Olsen, Thorbjørn Krejsgaard, Lise M. Lindahl, Charlotte Menne Bonefeld, Mariusz A. Wasik, Sergei B. Koralov, Carsten Geisler, Mogens Kilian, Lars Iversen, Anders Woetmann and Niels Odum

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Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

Thorbjørn Krejsgaard, Andreas Willerslev-Olsen, Lise M. Lindahl, Charlotte M. Bonefeld, Sergei B. Koralov, Carsten Geisler, Mariusz A. Wasik, Robert Gniadecki, Mogens Kilian, Lars Iversen, Anders Woetmann, and Niels Odum

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Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Andreas Willerslev-Olsen, Thorbjørn Krejsgaard, Lise M. Lindahl, Ivan V. Litvinov, Simon Fredholm, David L. Petersen, Claudia Nastasi, Robert Gniadecki, Nigel P. Mongan, Denis Sasseville, Mariusz A. Wasik, Charlotte M. Bonefeld, Carsten Geisler, Anders Woetmann, Lars Iversen, Mogens Kilian, Sergei B. Koralov, and Niels Odum

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The authors thank K. Kaltoft for generously providing the CTCL cell lines. This work was supported in part by research funding from the Danish Cancer Society, the Carlsberg Foundation, Dansk Kræftforsknings Fond, the Danish Research Councils, the Danish National Advanced Technology Foundation (Innovationsfunden), the Copenhagen Cluster of Immunology, the Lundbeck Foundation, the Novo Nordic Foundation, the University of Copenhagen, and the National Cancer Institute (R01-CA96856 and CA89194).