Single cell transcriptomics of human psoriasis and epidermal specific Ube2l3 deficient mice highlight CXCL16/CXCR6 involvement in psoriasis development

Psoriasis is a chronic, complex immune-mediated inflammatory disorder with cutaneous and systemic manifestations in which keratinocytes, dendritic cells and T cells have central roles. UBE2L3 may be a protective biomarker that regulates the pathogenesis of psoriasis. Here, we identify the IL-17A signaling similarity between human psoriatic skin and Ube2l3 conditional knockout mouse skin in the epidermis rather than dermis. IL-17A is regulated by CXCR6⁺ Vγ2⁺ γδT cells in mouse while CXCR6⁺ CD8⁺ T cells in human. CXCL16 is the only chemokine that binds to and stimulates CXCR6. Ube2l3 reduction in keratinocytes activates IL-1β and then promotes CXCL16 expression through STAT3 signaling. Up-regulated CXCL16 in keratinocytes and cDC2/mDC then attracts Vγ2⁺ γδT17 or CD8⁺ T cells to secrete IL-17A and form a positive feedback loop in keratinocytes supporting psoriatic lesions. Thus, UBE2L3 is a keratinocyte-intrinsic suppressor of epidermal IL-17 production in Vγ2⁺ γδT cells in mouse and CD8⁺ T cells in human through the CXCL16/CXCR6 signaling pathway in psoriasis.