CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells

Human CD4+FoxP3+ T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4+CD25+ and CD4+CD25− T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4+CD25+ cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA+) and activated (CD45RO+) subsets within the FoxP3+ T-cell population. Sorting of regulatory T cells into CD147− and CD147+ populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO+ Treg subset. When analyzing CD4+ T cells for their cytokine producing potential, CD147 levels grouped the FoxP3+ subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4+FoxP3+ subset and may provide means to manipulate cells important for immune homeostasis.