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


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.
    Full-text · Article · Aug 2012 · Frontiers in Immunology
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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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    ABSTRACT: Regulatory T cells (Tregs) are essential for controlling peripheral tolerance by the active suppression of various immune cells including conventional T effector cells (Teffs). Downstream of the T cell receptor (TCR), more than 500 protein kinases encoded by the human genome have to be considered in signaling cascades regulating the activation of Tregs and Teffs, respectively. Following TCR engagement, Tregs posses a number of unique attributes, such as constitutive expression of Foxp3, hyporesponsiveness and poor cytokine production. Furthermore, recent studies showed that altered regulation of protein kinases is important for Treg function. These data indicate that signaling pathways in Tregs are distinctly organized and alterations at the level of protein kinases contribute to the unique Treg phenotype. However, kinase-based signaling networks in Tregs are poorly understood and necessitate further systematic characterization. In this study, we analyzed the differential expression of kinases in Tregs and Teffs by using a kinase-selective proteome strategy. In total, we revealed quantitative information on 185 kinases expressed in the human CD4(+) T cell subsets. The majority of kinases was equally abundant in both T cell subsets, but 11 kinases were differentially expressed in Tregs. Most strikingly, Tregs showed an altered expression of cell cycle kinases including CDK6. Quantitative proteomics generates first comparative insight into the kinase complements of the CD4(+) Teff and Treg subset. Treg-specific expression pattern of 11 protein kinases substantiate the current opinion that TCR-mediated signaling cascades are altered in Tregs and further suggests that Tregs exhibit significant specificities in cell-cycle control and progression.
    Preview · Article · Jul 2012 · PLoS ONE
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    ABSTRACT: The immune system is a highly balanced network of different cell types. This balance is disturbed in the setting of organ or stem cell transplantation, which can lead to graft rejection or "Graft versus host disease" (GvHD). Conventional pharmacological treatment by broad immune suppression is restricted by dose-limiting side effects. A novel strategy for prevention and control is cell therapy. This applies particularly to GvHD. A number of phase I trials have already been launched. The most appropriate cell type appears to be the regulatory T (Treg) cell as it is a natural "suppressor" of the immune system. Treg cells are able to inhibit various effector cells including CD4+ and CD8+ T cells, the main drivers of GvHD. Like other T cells, also Treg cells can be divided into naïve and memory-type cells. We have previously identified effector/memory Treg cells (T(REM)), the regulatory counterparts of CD4+ effector/memory T cells (T(EM)). T(REM) may be particularly suited to inhibit proinflammatory reactions in peripheral tissues as they express the chemokine receptor CCR6, a feature they share with proinflammatory Th17 cells. As specific marker, they also express CD39 but lack the expression of CD49d and CD127. We could show that a simple depletion of CD49d and CD127 expressing cells yields a population of "untouched" Treg cells that is highly pure and largely consist of highly suppressive T(REM) cells. Mouse models have confirmed the efficacy of Treg cells in controlling GvHD but the translation has been lagging. First clinical trials suggesting safety of adoptive Treg transfer increase the need for methods that allow obtaining clinical-grade Treg cells in sufficient amounts. The new approach may therefore provide a promising new alternative to facilitate a simple access to these cells.
    No preview · Article · Mar 2012 · Immunologic Research
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