Deficient Cutaneous Antibacterial Competence in Cutaneous T-Cell Lymphomas: Role of Th2-Mediated Biased Th17 Function

Abstract

Purpose: Primary cutaneous T-cell lymphomas (CTCL) are neoplastic disorders of skin-homing T cells. Affected skin areas show morphologic similarities with alterations in other T-cell-mediated dermatoses. Furthermore, as in atopic dermatitis but in contrast with psoriasis, patients with CTCL are frequently afflicted by cutaneous bacterial infections that support the survival of lymphoma cells. Our aim was to investigate the mechanisms of elevated susceptibility to cutaneous infections in patients with CTCL.Experimental Design: Skin samples from CTCL, psoriasis, and atopic dermatitis patients were used to illuminate the antibacterial competence status and the presence of its modulating cytokines. For substantiation of findings, 3-dimensional epidermis models, isolated and in vitro generated Th-subpopulations, were applied. Parameters were analyzed via qPCR and IHC.Results: CTCL lesions compared with psoriatic lesions presented an impaired upregulation of antibacterial proteins (ABPs), with levels even below those in atopic dermatitis. This was associated with a relative deficiency of the ABP-inducing cytokine IL-17 and a strong presence of the ABP-downregulating cytokine IL-13. The simultaneous presence of the Th17-cell cytokine IL-26 indicated that IL-17 deficiency in CTCL lesions results from functional deviation of Th17 cells. Accordingly, IL-17 but not IL-26 production by Th17 cells in vitro was inhibited by IL-4Ra ligand. Levels of other ABP inducers were comparable between CTCL and psoriasis lesions. The same was true about IL-22/TNF-a targets, including the keratinocyte hyperregeneration marker K16 and the matrix-degrading enzyme MMP1.Conclusion: Our results suggest that the cutaneous bacterial infections in CTCL are caused by impaired ABP induction as consequence of Th2-mediated biased Th17-cell function. Clin Cancer Res; 20(21); 5507-16. Ó2014 AACR.

Interleukin-26: An Emerging Player in Host Defense and Inflammation

“…This observation suggests that IL-26 drives a functional and positive feedback loop, by which its signaling sustainability and influence on inflammation is preserved. This finding was recently verified and expanded when a functional deviation of Th17 cells was demonstrated in vitro when IL-4Rα stimulation (the receptor subunit shared by IL-4 and IL-13) resulted in diminished IL-17F gene expression whilst the gene expression of IL-26 remained unaltered [19]. …”

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

“…Furthermore, it is likely that cytokines and factors other than IL-2Rg cytokines also influence toxin-mediated cross talk between malignant and nonmalignant T cells. Indeed, SEA triggers IL-10 expression in cocultures of malignant and nonmalignant T cells; 75 IL-13 inhibits IL-17, but not IL-22 and IL-26, expression by Th17 cells; 76 and prostaglandins (eg, prostaglandin E2) produced by malignant T cells are known to modulate differentiation and cytokine production by nonmalignant T cells. 75 Accordingly, our data suggest that an inclusion of nonmalignant T cells (and possibly stromal cells and keratinocytes) into cultures of malignant T cells would critically improve future in vitro models of CTCL to better mimic the dynamic interactions seen in CTCL patients.…”

Recent advances in primary cutaneous T-cell lymphoma

“…In atopic dermatitis, reduced production of antimicrobial peptides in the skin accounts for frequent infections and impaired cutaneous immune response. Of interest are two studies by Suga et al and Wolk et al [30,31] that show lower expression levels of antimicrobial peptides in lesional CTCL skin. Beside tumor-derived galectins, low level of antimicrobial peptides in CTCL, as in atopic dermatitis, correlated with barrier dysfunction and frequent infections of the skin.…”