Keratinocytes present Staphylococcus aureus enterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma

Ziao Zeng, Chella Krishna Vadivel, Maria Gluud, Martin R J Namini, Lang Yan, Sana Ahmad, Morten Bagge Hansen, Jonathan Coquet, Tomas Mustelin, Sergei B Koralov, Charlotte Menne Bonefeld, Anders Woetmann, Carsten Geisler, Emmanuella Guenova, Maria R Kamstrup, Thomas Litman, Lise-Mette R Gjerdrum, Terkild B Buus*, Niels Ødum*

*Corresponding author af dette arbejde

Abstract

Cutaneous T-cell lymphoma is characterized by malignant T cells proliferating in a unique tumor microenvironment dominated by keratinocytes (KCs). Skin colonization and infection by Staphylococcus aureus are a common cause of morbidity and are suspected of fueling disease activity. In this study, we show that expression of HLA-DRs, high-affinity receptors for staphylococcal enterotoxins (SEs), by KCs correlates with IFN-γ expression in the tumor microenvironment. Importantly, IFN-γ induces HLA-DR, SE binding, and SE presentation by KCs to malignant T cells from patients with Sézary syndrome and malignant and nonmalignant T-cell lines derived from patients with Sézary syndrome and mycosis fungoides. Likewise, preincubation of KCs with supernatant from patient-derived SE-producing S aureus triggers proliferation in malignant T cells and cytokine release (including IL-2), when cultured with nonmalignant T cells. This is inhibited by pretreatment with engineered bacteriophage S aureus-specific endolysins. Furthermore, alteration in the HLA-DR-binding sites of SE type A and small interfering RNA-mediated knockdown of Jak3 and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that upon exposure to patient-derived S aureus and SE, KCs stimulate IL-2Rγ/Jak3-dependent proliferation of malignant and nonmalignant T cells in an environment with nonmalignant T cells. These findings suggest that KCs in the tumor microenvironment play a key role in S aureus-mediated disease activity in cutaneous T-cell lymphoma.

OriginalsprogEngelsk
TidsskriftThe Journal of investigative dermatology
ISSN0022-202X
DOI
StatusE-pub ahead of print - 16 maj 2024

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