Cell atlas of human psoriasis and epidermal specific Ube2l3 deficiency mouse highlighting CXCL16/CXCR6 orchestrating the development of psoriasis

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 identified the IL-17A signaling similarity between human psoriatic skin and Ube2l3 conditional knockout mouse skin in the epidermis rather than dermis. IL-17A was regulated by CXCR6 ⁺ Vγ2 ⁺ γδT in mouse while CXCR6 ⁺ CD8 ⁺ T in human. CXCL16 is the only chemokines whose bind to stimulate CXCR6. Ube2l3 reduction in keratinocytes activated IL-1β and then promote CXCL16 expression through STAT3 signaling. Up-regulated CXCL16 in keratinocytes and cDC2/mDC then attracted Vγ2 ⁺ γδT17 or CD8 ⁺ T to secrete IL-17A and form a positive feedback loop in keratinocytes supporting psoriatic lesion. Thus, UBE2L3 is a keratinocyte-intrinsic suppressor of epidermal IL-17 production in Vγ2 ⁺ γδT in mouse and CD8 ⁺ T in human through CXCL16/CXCR6 signaling pathway in psoriasis.