IL‐15 and IL‐23 synergize to trigger Th17 response by CLA⁺ T cells in psoriasis

Abstract

IL‐15 has emerged as a potentially relevant target in the IL‐17 response in psoriasis. However, its mechanism is poorly characterized in humans. IL‐15 and IL‐23 are constitutively expressed in the psoriatic lesion. Also, IL‐15 is considered a susceptibility‐associated gene in psoriasis, as are IL‐23R, and HLACW6. Here, we studied the effect of IL‐15 and IL‐23 stimulation on the cytokine response of CLA+/CLA‐ T cells from 9 psoriasis patients and 3 healthy control subjects. To this end, CLA + and CLA‐ T cells from blood samples were cultured with epidermal cells from skin biopsies and treated with IL‐15 and IL‐23. After five days of culture, cytokines in supernatant were measured by ELISA or fluorescent bead‐based immunoassay. There was a statistically significant increase in IL‐17F and IL‐17A production (P < .001) in cocultures of psoriasis skin‐homing CLA + T cells with epidermal cells when stimulated with IL‐15 and IL‐23, but this effect was not observed in the cells of healthy controls. Interestingly, this response was reduced by around 50 to 80% by blocking HLA class I and II molecules. Our results point to the synergic action of IL‐15 and IL‐23 selectively for CLA + cells in psoriasis, leading to the induction of Th17 cell‐related cytokines.

The Translational Relevance of Human Circulating Memory Cutaneous Lymphocyte-Associated Antigen Positive T Cells in Inflammatory Skin Disorders

“…IL-15 and IL-23, both present in psoriatic lesions, have been shown to synergize with CLA + T cells and autologous epidermal cells to produce IL-17A and IL-17F in PSO. This phenomenon occurs without the use of any exogenous stimulus, in a major histocompatibility complex (MHC)-dependent way, and independently of resident T cells (18), but it does not take place using CLA − T cells or cells from healthy controls. This is an example of how psoriatic skin cytokine microenvironment interacts specifically with skin-related memory T cells generating the IL-17 response critical for PSO initiation and maintenance.…”

Fostering a healthy culture: Biological relevance of in vitro and ex vivo skin models

“…This is not surprising, considering that humans and rodents are separated by an estimated 96 million years of evolution 21 . Addressing this fact, many studies are being conducted on patient‐derived primary skin cells, including human keratinocytes, 22‐25 melanocytes, 26‐30 fibroblasts 31‐34 and cell co‐cultures 35‐37 . However, typical in vitro culture conditions fail to replicate and, in fact, do not come close to imitating the biomechanical and biochemical complexity of the microenvironment in which cells exist and to which they respond to in native tissues.…”

“…Also, the co‐culture of dermal fibroblasts and keratinocytes can model particulate matter exposure, where factors released by keratinocytes after heavy metal and hydrocarbon exposure can mediate dermal collagen degradation 36 . In other examples, co‐cultures of vitiligo patient‐derived CD4 + and CD8 + T cells, 52 or keratinocytes and T cells from psoriasis patients, 37 can be used to advance our understanding of skin disease immunopathogenesis.…”

Recent progress at the psoriasis and atopic dermatitis research front: An experimental dermatology perspective

“…IL17 is one of the key effector molecules that promote a hyperproliferative response in keratinocytes, leading to uncontrolled epidermal expansion and psoriatic plaque formation 4,13,19,20 . IL15 has also emerged as a potential target in PSO 21 . Association between IL‐15 single nucleotide polymorphisms (SNPs) and PSO has been reported, 22 and an ex vivo co‐culture study found that IL15 synergizes with IL23 to activate cutaneous lymphocyte‐associated antigen (CLA)+ T cells to produce high levels of IL17A/F 21 .…”

“…IL15 has also emerged as a potential target in PSO 21 . Association between IL‐15 single nucleotide polymorphisms (SNPs) and PSO has been reported, 22 and an ex vivo co‐culture study found that IL15 synergizes with IL23 to activate cutaneous lymphocyte‐associated antigen (CLA)+ T cells to produce high levels of IL17A/F 21 . Compared to PSO, generalized pustular psoriasis expresses higher levels of IL1 and IL36 in the skin, 23 in addition to IL17 and IL23, leading to excessive and persistent skin inflammation that can manifest systemically 23 …”