Dermal gamma delta T cells play role in pathogenesis of psoriasis

Louisville, Ky. - Researchers have recently identified gamma delta T cells as having an important role in the pathogenesis of psoriasis. This considerable breakthrough in the pathogenesis of the disease could potentially have far-reaching implications in terms of more targeted therapies for psoriasis.

Psoriasis is one of the most common immune-mediated chronic inflammatory skin diseases but has a pathogenesis that is not completely understood. There is mounting evidence, however, that the disease is T-cell driven, specifically T helper (Th) 1 and Th17 cells, both of which have been shown to be involved in the pathogenesis of psoriasis. The pro-inflammatory cytokines produced by these T cells including tumor necrosis factor- alpha (TNF-alpha), interleukin (IL)-17, IL-22, IL-23, IL-12 and IL-1beta have all been implicated in the pathogenesis of the disease.

“New and emerging treatments for psoriasis such as novel biologic agents have been developed to selectively target specific components of the immune system, such as IL-23 and IL-17,” says Jun Yan, M.D., Ph.D., professor of medicine, endowed chair in Translational Research, co-director, Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY. “The dermal gamma delta T cells which are found to be intricately involved in these immune pathways could prove to be another viable target and a new focus for future therapies in psoriasis.”

A closer look

Dr. Yan and his colleagues recently conducted a study to identify and better understand which cells and pathways in the skin are the major contributors to the inflammation typically seen in psoriasis and psoriatic lesions. To dissect the precise cellular source of IL-23 and the transcripts of which are increased in human psoriasis, Dr. Yan analyzed skin tissues of healthy individuals and patients with psoriasis, as well as murine psoriasis skin samples using immunofluorescent staining.

According to Dr. Yan, IL-23-induced skin inflammation has been primarily linked to the function of TH17 cells and related cytokines. The results of the study not only showed that IL-23 is mainly produced by dermal dendritic cells and macrophages - which is critical for IL-17 production in the skin - but also that the dermal gamma delta T cells are the major source of IL-17 upon IL-23 stimulation in the skin. In addition, Dr. Yan found that the IL-17-producing dermal gamma delta T cells are phenotypically unique.

“From the mouse model point of view, gamma delta T cells are definitely more important than TH1 and Th17 cells, and appear to be essential in the production of IL-17 and pathogenic cells in the skin following IL-23 stimulation,” he says. “More importantly, these cells have also shown to be very much involved in the development of psoriasis. Therefore, a therapy that could specifically target and regulate dermal gamma delta T cells could be beneficial.”

Gamma delta T cell regulation

IL-23-induced changes in murine skin share many characteristics with human skin, Dr. Yan says, including erythema, acanthosis, parakeratosis and leukocyte infiltration. According to Dr. Yan, murine skin samples deficient of gamma delta T cells or IL-17 receptor significantly decreased IL-23-induced epidermal thickness and neutrophil infiltration, and subsequently showed decreased skin inflammation, psoriasis lesions, or psoriasis-related inflammation. This suggests gamma delta T cells are key in the development of psoriasis.

Similarly in human psoriasis skin samples, the study found that gamma delta T cells are the critical cells to produce IL-17, which were massively infiltrated in psoriatic skin, accounting for approximately 30 to 40 percent among the whole of the CD3+ cells. In humans, however, it is very difficult to dissect what the contribution is of Th17 cells, Th1 cells or gamma delta T cells into the disease, Dr. Yan says, and correlation studies can only be performed here.

“There is ongoing research looking at gamma delta T cells and what kind of factors could regulate those dermal gamma delta T cells in humans. It appears that this cell population would be a novel drug target for psoriasis therapy; however, it is hard to say when such a drug could become available,” he says. “Nevertheless, we now have a new focus for therapy in our sites, which eventually could translate into more effective treatments for psoriasis by reducing the inflammation typically seen in psoriasis and psoriatic skin.”

Disclosures: Dr. Yan reports no relevant financial interests.

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