CD8(+) T cells Mediate RAS-induced Psoriasis-like Skin Inflammation Through IFN-γ

The RAS signaling pathway is constitutively activated in psoriatic keratinocytes. We expressed activated H-RAS(V12G) in suprabasal keratinocytes of adult mice and observed rapid development of a psoriasis-like skin phenotype characterized by basal keratinocyte hyperproliferation, acanthosis, hyperkeratosis, intraepidermal neutrophil microabscesses and increased Th1/Th17 and Tc1/Tc17 skin infiltration. The majority of skin infiltrating CD8(+) T cells co-expressed IFN-γ and IL-17A. When RAS was expressed on a Rag1−/− background, microabscess formation, iNOS expression and keratinocyte hyperproliferation were suppressed. Depletion of CD8(+) but not CD4(+) T cells reduced cutaneous and systemic inflammation, the RAS-induced increase in cutaneous Th17 and IL-17(+) γΔ T cells, and epidermal hyperproliferation to levels similar to a Rag1−/− background. Reconstitution of Rag1−/− inducible RAS mice with purified CD8(+) T cells restored microabscess formation and epidermal hyperproliferation. Neutralization of IFN-γ but not IL-17A in CD8(+) T cell reconstituted Rag1−/− mice expressing RAS blocked CD8-mediated skin inflammation, iNOS expression and keratinocyte hyperproliferation. These results show for that CD8(+) T cells can orchestrate skin inflammation with psoriasis-like pathology in response to constitutive RAS activation in keratinocytes, and this is primarily mediated through IFN-γ.