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

Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Oslo, Norway.
Blood (Impact Factor: 10.45). 09/2011; 118(19):5141-51. DOI: 10.1182/blood-2011-02-339242
Source: PubMed

ABSTRACT 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.

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    • "A detailed knowledge of human FOXP3 + cell subsets is essential for a better understanding of the regulation of human FOXP3 expression, the study of abnormalities among the FOXP3 + subpopulations in autoimmune diseases and allergies, and the selection and purification of the most promising subpopulation(s) of Treg cells for in vitro expansion and adoptive transfer (Fujii et al., 2011; Miyara and Sakaguchi, 2011). Recent studies from different groups have demonstrated the heterogeneity of human FOXP3 + cells and have begun to define and characterize possible subsets (Baecher-Allan et al., 2001; Ito et al., 2008; Thornton et al., 2010; Akimova et al., 2011; Bianchini et al., 2011; Schuler et al., 2011; Solstad et al., 2011; Duhen et al., 2012). "
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    ABSTRACT: The human CD4(+)FOXP3(+) T cell population is heterogeneous and consists of various subpopulations which remain poorly defined. Anergy and suppression are two main functional characteristics of FOXP3(+)Treg cells. We used the anergic behavior of FOXP3(+)Treg cells for a better discrimination and characterization of such subpopulations. We compared IL-2-expressing with IL-2-non-expressing cells within the memory FOXP3(+) T cell population. In contrast to IL-2-non-expressing FOXP3(+) cells, IL-2-expressing FOXP3(+) cells exhibit intermediate characteristics of Treg and Th cells concerning the Treg cell markers CD25, GITR, and Helios. Besides lower levels of FOXP3, they also have higher levels of the transcription factors NFATc2, c-Fos, NF-κBp65, and c-Jun. An approach combining flow cytometric measurements with statistical interpretation for quantitative transcription factor analysis suggests that the physiological expression levels not only of FOXP3 but also of NFATc2, c-Jun, c-Fos, and NF-κBp65 are limiting for the decision whether IL-2 is expressed or not in activated peripheral human memory FOXP3(+) cells. These findings demonstrate that concomitant high levels of NFATc2, c-Jun, c-Fos, and NF-κBp65 lead in addition to potential IL-2 expression in those FOXP3(+) cells with low levels of FOXP3. We hypothesize that not only the level of FOXP3 expression but also the amounts of the four transcription factors studied represent determining factors for the anergic phenotype of FOXP3(+) Treg cells.
    Frontiers in Immunology 08/2012; 3:264. DOI:10.3389/fimmu.2012.00264
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    • "On the other hand, comparative proteome analysis necessitates substantial cell amounts and thus was hindered by the scarcity of CD4+CD25highFoxp3+ Tregs and their poor proliferation in vitro. Nevertheless, two proteome studies have compared protein expression in human Tregs and Teffs isolated from leukapheresis and buffy coat products [29], [30]. In total, these studies have identified Galectin-10 and CD147 (Basigin/Emmprin) as Treg-specific marker proteins, but provided no information about low abundant protein kinases at all. "
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    Immunologic Research 03/2012; 53(1-3):200-12. DOI:10.1007/s12026-012-8267-9 · 3.10 Impact Factor
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