The Macrophage Galactose-Type C-Type Lectin (MGL) Modulates Regulatory T Cell Functions.
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In this study, we demonstrate that Treg immunosuppressive activity can be modulated by the cross-linking between the CD45RA expressed by Tregs and the C-type lectin MGL.This effect can be attributed to changes in CD45RA and TCR signalling through the inhibition of Lck and inactivation of Zap-70, an increase in the Foxp3 methylation status and, ultimately, the reduced production of suppressive cytokines.These results indicate a role of MGL as an immunomodulator within the tumour microenvironment interfering with Treg functions, suggesting its possible use in the design of anticancer vaccines.
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PubMed Central - PubMed
Affiliation: Department of Experimental Medicine, "Sapienza" University, Rome, Italy.
ABSTRACT
Regulatory T cells (Tregs) are physiologically designed to prevent autoimmune disease and maintain self-tolerance. In tumour microenvironments, their presence is related to a poor prognosis, and they influence the therapeutic outcome due to their capacity to suppress the immune response by cell-cell contact and to release immunosuppressive cytokines. In this study, we demonstrate that Treg immunosuppressive activity can be modulated by the cross-linking between the CD45RA expressed by Tregs and the C-type lectin MGL. This specific interaction strongly decreases the immunosuppressive activity of Tregs, restoring the proliferative capacity of co-cultured T lymphocytes. This effect can be attributed to changes in CD45RA and TCR signalling through the inhibition of Lck and inactivation of Zap-70, an increase in the Foxp3 methylation status and, ultimately, the reduced production of suppressive cytokines. These results indicate a role of MGL as an immunomodulator within the tumour microenvironment interfering with Treg functions, suggesting its possible use in the design of anticancer vaccines. No MeSH data available. Related in: MedlinePlus |
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pone.0132617.g001: MGL recognises CD45RA on human Tregs and modulates their suppressive capacity.(A) Flow cytometry analysis of purified Treg stained with anti- CD4, CD25, FOXP3 and CD45RA antibodies. (B) Competition studies of rhMGL-Fc binding to CD45RA expressed by Tregs using GalNAc polymer. Filled histograms represent the untreated Tregs, while the open histograms show Tregs treated with rhMGL-Fc or rhMGL-Fc+GalNAc. (C) Western blot analysis of Treg lysate immunoprecipitated with rhMGL-Fc. Samples were run in 4–12% SDS-PAGE gel and were analysed with anti-CD45RA and rhMGL-Fc. These results are representative of one donor out of three. (D) Immunosuppression capacity of Tregs alone and Tregs treated with rhMGL-Fc after four days of co-culture with CD4+ CD25- T cells (ratio 1:5, Treg:CD4+CD25- T cells), in presence of anti-CD3 and anti-CD28. (E) IFNγ spots produced by CD8+ T cells (5×104/well) stimulated with mDCs in presence or not of Tregs ± rhMGL. The results correspond with the mean of three independent experiments ± standard deviation (SD). * corresponds to p<0.05 and ** to p<0.01. Mentions: Tregs were isolated from PBMCs and characterised as shown in Fig 1A. After purification, we obtained 92% of Tregs (CD4+CD25+FOXP3+) of which 70% were positive for CD45RA. |
View Article: PubMed Central - PubMed
Affiliation: Department of Experimental Medicine, "Sapienza" University, Rome, Italy.
No MeSH data available.