Matrix Metalloproteinase-2 Conditions Human Dendritic Cells to Prime Inflammatory TH2 Cells via an IL-12- and OX40L-Dependent Pathway

SummaryMatrix 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 TH2 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 TH2 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (300 K)Download as PowerPoint slideHighlights► MMP-2-specific CD4+ T cell responses present in melanoma patients (TILs) ► MMP-2-specific CD4+ T cells display an inflammatory TH2 phenotype ► Active MMP-2 locally skews T cell differentiation toward suboptimal TH2 responses ► Active MMP-2 induces TH2 skewing by blocking IL-12 and inducing OX40L on DCs