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Keratinocytes present Staphylococcus aureusenterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma
- Source :
- Journal of Investigative Dermatology; 20240101, Issue: Preprints
- Publication Year :
- 2024
-
Abstract
- Cutaneous T-cell lymphoma (CTCL) is characterized by malignant T-cells proliferating in a unique tumor microenvironment (TME) dominated by keratinocytes. Skin colonization and infection by Staphylococcus aureus(S. aureus) is a common cause of morbidity and suspected of fueling disease activity. Here we show that expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes correlates with IFN-γ expression in the TME. Importantly, IFN-γ induces HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. Likewise, preincubation of keratinocytes with supernatant from patient-derived SE-producing S. aureustriggers proliferation in malignant T-cells and cytokine release (including IL-2), when cultured with non-malignant T-cells. This is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. Furthermore, mutations in the HLA-DR binding sites of SE type-A, and siRNA-mediated knockdown of Janus Kinase-3 (JAK3) and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that, upon exposure to patient-derived S. aureusand SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureusmediated disease activity in CTCL.
Details
- Language :
- English
- ISSN :
- 0022202X and 15231747
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Investigative Dermatology
- Publication Type :
- Periodical
- Accession number :
- ejs66388145
- Full Text :
- https://doi.org/10.1016/j.jid.2024.04.018