Epidermal γδ T cells expressing TNFR2 adopt an IL-17 phenotype in psoriasis, revealing new therapeutic targets.

Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the global population, characterized by keratinocyte hyperproliferation and immune cell infiltration. Current therapeutic strategies often target the TNF-α/IL-17 axis to mitigate inflammation. While the roles of dermal αß and γδ T cells in IL-17 production are relatively well-understood, the specific contributions of resident epidermal T cells, particularly γδ T cells, remain less clear. This gap in knowledge limits the development of more precise immunotherapies.

Researchers investigated the role of TNF-α in modulating epidermal γδ T cell activation and function, specifically focusing on TNFR1 and TNFR2 expression. They examined how TNF-α stimulation impacts cytokine and chemokine production by these cells. The study also assessed the necessity of TNFR1 and TNFR2 for epidermal γδ T cell development and homing to the skin, ultimately characterizing their functional contribution to the Tγδ17 phenotype in psoriasis.

A distinct subset of activated epidermal γδ T cells was found to express TNFR2, often co-expressed with TNFR1. Stimulation with TNF-α directly induced these epidermal γδ T cells to produce IL-17 family cytokines and various chemokines, highlighting their pro-inflammatory potential. Importantly, the study determined that neither TNFR1 nor TNFR2 is essential for the initial development or homing of epidermal γδ T cells to the skin. Instead, TNFR2 specifically plays a crucial role in shaping the function of epidermal γδ T cells, actively skewing them towards a Tγδ17 pro-inflammatory phenotype during the course of psoriasis. This indicates a direct mechanistic link between TNFR2 signaling and the pathogenic IL-17 signature in epidermal T cells.