γδ T cells and Th17 collaborate in CD18hypo PL/J psoriasiform dermatitis (P3139)

Abstract

Abstract The contribution of IL-17 to the pathogenesis of psoriasis is substantiated by the therapeutic efficacy of antibodies against the common p40 subunit of IL-12 and IL-23, like Ustekinumab, suppressing Th17 and Th1 signature cytokine production. To dissect the roles of distinct IL-17 producing T cell subsets in psoriasis, we systematically analyzed the occurrence of γδ and CD4+ T cells in blood, lymph nodes and skin of CD18hypo PL/J mice, developing psoriasiform dermatitis at 12-14 weeks of age due to reduced expression of CD18/β2 integrin to 2-16% of wild-type levels, and assessed the effects of blocking different targets within the IL-23/IL-17 axis. Severity of CD18hypo PL/J psoriasiform dermatitis correlated with a loss of skin-resident Vγ5+ T cells and concurrent skin infiltration with inflammatory γδTCRlow cells preceded by increases in Vγ4+ T cells in local lymph nodes. Moreover, inflammatory CD18hypo PL/J γδ T cells enhanced allogeneic CD4+ T cell responses in vitro. Injection of diseased CD18hypo PL/J mice with anti-γδTCR, -IL-17, and -IL-23/p19 antibodies resulted in resolution of skin inflammation and eliminated pathological γδ T cells. These results for the first time demonstrate a critical function of pathological skin-infiltrating γδ T cells in a complex psoriasis model and of wild-type CD18 levels in their suppression.