Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma

Abstract

In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells.

Figure 1

Schematic illustration of the antigen presenting cells (APC) antigen presentation and cytokine release together with the subsequent induction of different lymphocyte helper subsets. (1) The APC delivers three signals required for successful lymphocyte activation; antigen presentation, co-stimulation and cytokine release with cytokines being the major determinant of lymphocyte subset induction; (2) Additionally dendritic cells DC are able to induce a regulatory phenotype either by the absence of co-stimulation (immature DC’s lack CD80/86) or by activation of lymphocytes in a regulatory cytokine environment (tolerogenic DC’s).

Figure 2

Schematic illustration of the transition from a state of tumor equilibrium to a state of tumor immune privilege. The tumor equilibrium state (1) is characterized by T cell- and cytokine-mediated control of tumor progression. Conversely, the state of tumor immune privilege (2) is predominated by regulatory signals and cytokines allowing for immune evasion and tumor progression and metastasis. (Yellow: DC; blue: nonmalignant T cell; red: malignant T cell).

Figure 3

Schematic illustration of SE-mediated cross-talk between malignant and non-malignant T cells. Malignant T cells often display deficient expression and function of the TCR/CD3 complex and may not respond directly to bacterial superantigens such as staphylococcal enterotoxins (SE). Instead, malignant T cells often express MHC class II molecules, which are high-affinity receptors for SE (1). Non-malignant T cells with the appropriate Vb TCR respond to SE presented by malignant T cells (2, 3) or by antigen presenting cells (APC) (not shown). SE-mediated cross-talk between malignant and non-malignant T cells triggers cell-to-cell contact and production of growth factors, which in turn promote proliferation of malignant T cells (3) [104].