Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway

Cancer Cell. 2011 Mar 8;19(3):333-46. doi: 10.1016/j.ccr.2011.01.037.

Abstract

Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • GATA3 Transcription Factor / immunology
  • GATA3 Transcription Factor / metabolism
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Interleukin-13 / immunology
  • Interleukin-13 / metabolism
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Matrix Metalloproteinase 2 / immunology*
  • Matrix Metalloproteinase 2 / metabolism
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Models, Immunological
  • OX40 Ligand / immunology*
  • OX40 Ligand / metabolism
  • Signal Transduction / immunology*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • GATA3 Transcription Factor
  • Inflammation Mediators
  • Interleukin-13
  • OX40 Ligand
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interleukin-4
  • Matrix Metalloproteinase 2