Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4+ T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis.

Herpes simplex virus-type 1 (HSV-1) causes the majority of cutaneous viral infections. Viral infections are controlled by the immune system, and CD8(+) cytotoxic T-lymphocytes (CTLs) have been shown to be crucial during the clearance of HSV-1 infections. Although epidermal Langerhans cells (LCs) are the first dendritic cells (DCs) to come into contact with the virus, it has been shown that the processing of viral antigens and the differentiation of antiviral CTLs are mediated by migratory CD103(+) dermal DCs and CD8α(+) lymph node-resident DCs. In vivo regulatory T-cells (Tregs) are implicated in the regulation of antiviral immunity and we have shown that signaling via the receptor activator of NF-κB (RANK) and its ligand RANKL mediates the peripheral expansion of Tregs. However, in addition to expanding Tregs, RANK-RANKL interactions are involved in the control of antimicrobial immunity by upregulating the priming of CD4(+) effector T cells in LCMV infection or by the generation of parasite-specific CD8(+) T cells in Trypanosoma cruzi infection. Here, we demonstrate that cutaneous RANK-RANKL signaling is critical for the induction of CD8-mediated antiviral immune responses during HSV-1 infection of the skin by preventing virus-induced LC apoptosis, improving antigen transport to regional lymph nodes, and increasing the CTL priming capacity of lymph node DCs.

Event Abstract Back to Event Alpha-melanocyte-stimulating hormone (α-MSH) inhibits the development and progression of autoimmune encephalomyelitis by generating functional regulatory T cells Nadine Sucker1*, Lars Klenner1, Sandra Laggies1, Christina Bürger1, Thomas A. Luger1 and Karin Loser1 1 University of Münster, Department of Dermatology, Germany The neuropeptide α-MSH is a potent immunomodulator capable of inducing immunosuppression and tolerance. Using the mouse model of experimental autoimmune encephalomyelitis (EAE) we systemically treated MOG-immunized mice with α-MSH before and after the onset of hind limb paralysis. Whereas control mice showed a significant weight loss and developed severe ascending paralysis, mice preemptively injected with α-MSH were resistant to EAE development. Notably, therapeutic treatment attenuated EAE progression and prevented mice from weight loss. Flow cytometry, immunofluorescence staining and gene expression analyses revealed the absence of pathogenic Th17 and Th1 cells from brain tissue of α-MSH-treated animals. This effect was mediated by up-regulated numbers of Foxp3+ regulatory T cells (Treg) in α-MSH-injected mice versus controls. Since α-MSH has been shown to expand Treg by the induction of tolerogenic dendritic cells (DC) we analyzed the DC phenotype at different stages of disease. DC from α-MSH-treated mice expressed increased levels of PD-L1 or IL 10 and down-regulated maturation markers pointing to the induction of a tolerogenic DC phenotype. Since signaling via melanocortin-1-receptor (MC-1R) mediates the immunomodulatory effects of α-MSH we induced EAE in MC-1R-deficient mice. Interestingly, upon α-MSH injection these mice developed hind limb paralysis similar to PBS treated controls demonstrating that binding to MC-1R is essential for the α MSH-mediated prevention of EAE. Together, these data indicate that α MSH induces tolerogenic DC and expands functional Treg in vivo. These Treg suppress pathogenic Th1 and Th17 cells during EAE development, suggesting α-MSH as potential therapeutic option for the treatment of patients with moderate multiple sclerosis. Keywords: α-MSH, protection, Experimental autoimmune encephalomyelitis, Treg, Th1 Cells, Th17 Cells Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Sucker N, Klenner L, Laggies S, Bürger C, Luger T and Loser K (2013). Alpha-melanocyte-stimulating hormone (α-MSH) inhibits the development and progression of autoimmune encephalomyelitis by generating functional regulatory T cells. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00112 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Miss. Nadine Sucker, University of Münster, Department of Dermatology, Münster, 48149, Germany, nadine.sucker@ukmuenster.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nadine Sucker Lars Klenner Sandra Laggies Christina Bürger Thomas A. Luger Karin Loser Google Nadine Sucker Lars Klenner Sandra Laggies Christina Bürger Thomas A. Luger Karin Loser Google Scholar Nadine Sucker Lars Klenner Sandra Laggies Christina Bürger Thomas A. Luger Karin Loser PubMed Nadine Sucker Lars Klenner Sandra Laggies Christina Bürger Thomas A. Luger Karin Loser Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The neuropeptide a-melanocyte-stimulating hormone (alpha-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that a-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying alpha-MSH-induced immunosuppression, we investigated whether a-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that a-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those a-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, alpha-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via alpha-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that a-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis. Journal of Investigative Dermatology (2012) 132, 1814-1824; doi:10.1038/jid.2012.59; published online 15 March 2012

Mechanisms linking innate immunity and autoimmune responses are poorly understood. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.

BACKGROUND:The neuropeptide alpha-melanocyte-stimulating hormone is well known as a mediator of skin pigmentation. More recently, it has been shown that alpha-melanocyte-stimulating hormone also plays pivotal roles in energy homeostasis, sexual function, and inflammation or immunomodulation. Alpha-melanocyte-stimulating hormone exerts its antiinflammatory and immunomodulatory effects by binding to the melanocortin-1 receptor, and since T cells are important effectors during immune responses, we investigated the effects of alpha-melanocyte-stimulating hormone on T cell function.METHODOLOGY/PRINCIPAL FINDINGS:T cells were treated with alpha-melanocyte-stimulating hormone, and subsequently, their phenotype and function was analyzed in a contact allergy as well as a melanoma model. Furthermore, the relevance of alpha-melanocyte-stimulating hormone-mediated signaling for the induction of cytotoxicity was assessed in CD8(+) T cells from melanoma patients with functional and nonfunctional melanocortin-1 receptors. Here we demonstrate that the melanocortin-1 receptor is expressed by murine as well as human CD8(+) T cells, and we furthermore show that alpha-melanocyte-stimulating hormone/melanocortin-1 receptor-mediated signaling is critical for the induction of cytotoxicity in human and murine CD8(+) T cells. Upon adoptive transfer, alpha-melanocyte-stimulating hormone-treated murine CD8(+) T cells significantly reduced contact allergy responses in recipient mice. Additionally, the presented data indicate that alpha-melanocyte-stimulating hormone via signaling through a functional melanocortin-1 receptor augmented antitumoral immunity by up-regulating the expression of cytotoxic genes and enhancing the cytolytic activity in tumor-specific CD8(+) T cells.CONCLUSIONS/SIGNIFICANCE:Together, these results point to an important role of alpha-melanocyte-stimulating hormone in MHC class I-restricted cytotoxicity. Therefore, treatment of contact allergies or skin cancer with alpha-melanocyte-stimulating hormone or other more stable agonists of melanocortin-1 receptor might ameliorate disease or improve antitumoral immune responses.