Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which are characterized by their capability to suppress T-cell responses. While MDSCs have been traditionally associated with cancer diseases, their role as regulators of autoimmune diseases is emerging. Pemphigus is a chronic autoimmune blistering skin disease characterized by dysregulated T-cell responses and autoantibody production. The role of MDSCs in pemphigus disease has not been defined yet. The aim of this study was to characterize MDSCs in pemphigus patients and to dissect their relationship with CD4+ T-cell subsets and clinical disease assessments. For this purpose, we performed a cross-sectional analysis of 20 patients with pemphigus. Our results indicate that a population of CD66b+ CD11b+ polymorphonuclear-like MDSCs (PMN-MDSCs) is expanded in the peripheral blood mononuclear cell fraction of pemphigus patients compared to age-matched healthy donors. These PMN-MDSCs have the capability of suppressing allogeneic T-cell proliferation in vitro and show increased expression of characteristic effector molecules such as arginase I and interleukin-10. We further demonstrate that PMN-MDSCs are especially expanded in patients with active pemphigus, but not in patients in remission. Moreover, MDSC frequencies correlate with an increased Th2/Th1 cell ratio. In conclusion, the identification of a functional PMN-MDSC population suggests a possible role of these cells as regulators of Th cell responses in pemphigus.

Psoriasis is a Th17-mediated chronic inflammatory skin disease with aberrant keratinocyte proliferation and differentiation. Th17 cytokines like IL-17, IL-22 and IL-23 are critically involved in psoriasis pathogenesis that results in epidermal thickening and production of innate factors such as antimicrobial peptides. Topical treatment of psoriasis with anthralin is highly effective although the exact mode of action of this drug in psoriasis is not fully understood. We aimed to study the direct effects of anthralin on keratinocyte proliferation, differentiation and production of innate factors like antimicrobial factors. To test the effects of anthralin we used (1) primary keratinocytes, (2) a 3D psoriasis tissue models and (3) skin biopsies from patients treated with anthralin. In addition we studied the effects of anthralin in monolayer and multilayer keratinocyte cultures stimulated with IL-17A and IL-22. Anthralin directly induced cell apoptosis in vitro in monolayer cultures but not in multilayer cultures treated with IL-17A and IL-22. Yet, keratinocyte proliferation was impaired by anthralin in vitro and in vivo. In lesional skin anthralin rapidly normalized cytokeratin (CK)16 expression. Moreover, anthralin suppressed DEFB4 expression in vitro and in vivo, while other antimicrobial peptides and innate cytokines studied like IL-6 and IL-8 were regulated differently in vitro and in vivo. Taken together anthralin has direct effects on keratinocytes beyond the impairment of proliferation. CK16 and DEFB4 expression by keratinocytes were both suppressed by anthralin.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterized by their ability to suppress T-cell responses. Recently, we demonstrated that the human-pathogenic fungi Candida albicans and Aspergillus fumigatus induced a distinct subset of neutrophilic MDSCs. To dissect Candida-mediated MDSC induction in more depth, we studied the relative efficacy of different pathogenic non-albicans Candida species to induce and functionally modulate neutrophilic MDSCs, including C. glabrata, C. parapsilosis, C. dubliniensis, and C. krusei. Our data demonstrate that the extent of MDSC generation is largely dependent on the Candida species with MDSCs induced by C. krusei and C. glabrata showing a higher suppressive activity compared to MDSCs induced by C. albicans. In summary, these studies show that fungal MDSC induction is differentially regulated at the species level and differentially affects effector T-cell responses.

Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.