Staphylococcus aureus Augments Epithelial Skin Barrier Damage Through T Cell Activation in Cutaneous T Cell Lymphoma

Abstract

<div><h3>Background</h3><p>Skin barrier dysfunction is central to inflammation and susceptibility to infection in atopic dermatitis (AD). Cutaneous T-cell lymphoma (CTCL) shares clinical similarities with AD and is also associated with a high prevalence of <em>Staphylococcus aureus</em> (<em>S. aureus</em>) colonisation. However, the mechanisms driving skin barrier damage in CTCL and the contribution of bacteria remain poorly understood.</p><h3>Methods</h3><p>We investigate how the interplay between <em>S. aureus</em> (and staphylococcal enterotoxins (SEs)) and primary malignant- and non-malignant T cells affects keratinocyte expression of skin barrier proteins; in vitro, in an EL4 murine lymphoma model of bacteria-driven tumour progression, and in CTCL patient lesions colonised with SE-producing <em>S. aureus</em> before and after bacterial eradication by antibiotic treatment.</p><h3>Results</h3><p><em>S. aureus</em> and SEs activate malignant and non-malignant T cells to release barrier-repressing cytokines, including IL-4, IL-13, IL-22, and OSM, and JAK-dependent downregulation of filaggrin and loricrin in keratinocytes. In the EL4 model, bacteria-colonised tumour-bearing mice show significant filaggrin loss in tumour-adjacent epidermis, whereas antibiotic-treated mice maintain near-normal expression. Clinically, antibiotic eradication of SE-producing <em>S. aureus</em> partially restores filaggrin and loricrin expression in three of four patients, paralleling reduced inflammatory signalling.<br></p><h3>Conclusions</h3><p>SE-producing <em>S. aureus</em> promotes skin barrier impairment in CTCL through cytokine-driven, JAK-dependent repression of structural proteins in keratinocytes. These findings identify microbial–immune crosstalk as a contributor to CTCL skin pathology and provide mechanistic rationale for strategies targeting <em>S. aureus</em> colonisation as adjunctive therapy in CTCL.</p></div>