CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ

Andrew J. Gunderson, Javed Mohammed, Frank J. Horvath, Michael A. Podolsky, Cherie R. Anderson, Adam B. Glick

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 T helper type 1 (Th1)/Th17 and T cell type 1 (Tc1)/Tc17 skin infiltration. The majority of skin-infiltrating CD8 + T cells coexpressed IFN-γ and IL-17A. When RAS was expressed on a Rag1-/- background, microabscess formation, inducible nitric oxide synthase 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 of IL-17A, in CD8 + T-cell-reconstituted Rag1-/- mice expressing RAS blocked CD8-mediated skin inflammation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation. These results show 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.

Original languageEnglish (US)
Pages (from-to)955-963
Number of pages9
JournalJournal of Investigative Dermatology
Volume133
Issue number4
DOIs
StatePublished - Apr 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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