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Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10

Abstract

Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.

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Figure 1: Galectin-1 interferes with human DC differentiation and function.
Figure 2: Galectin-1 imparts a regulatory program in human mature DCs.
Figure 3: Galectin-1 endows mouse DCs with IL-27-dependent tolerogenic potential.
Figure 4: Galectin-1-induced regulatory DCs foster a tolerant microenvironment in antigen-specific and neoplastic settings.
Figure 5: Galectin-1-differentiated DCs suppress TH-17- and TH1-mediated neuroinflammation via IL-27 and IL-10.
Figure 6: Galectin-1 expression is higher during the peak and resolution of autoimmune inflammation and after exposure to tolerogenic stimuli.
Figure 7: Endogenous galectin-1 'fine tunes' the tolerogenic function of DCs.
Figure 8: Galectin-1-sufficient tolerogenic DCs contribute to the resolution of EAE.

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Acknowledgements

We thank F. Poirier (Institut Jacques Monod) for Lgals1−/− mice; C.J. Saris (Amgen) for Il27ra−/− mice; H. Rosenberg (National Institutes of Health) for critical reading of the manuscript; L. Baum (University of California at Los Angeles) for plasmids; M. Doenhoff (University of Nottingham) for endotoxin-free SEA; J. Correale, N. Rubinstein, S. Blois and N. Zwirner for advice; M. Barboza and J. Stupirski for technical assistance; C. Ricordi for support; the staff of the Animal Facilities of the Institute of Biology and Experimental Medicine and the Faculty of Exact and Natural Sciences (University of Buenos Aires); and the Ferioli and Ostry families for donations. Dedicated to the memory of E. Massouh. Supported by The National Agency for Promotion of Science and Technology (Argentina), Sales Foundation for Cancer Research (Argentina), National Council of Scientific and Technical Investigation (Argentina), University of Buenos Aires (Argentina), Fiorini Foundation (Argentina), Cancer Research Institute (USA), Mizutani Foundation for Glycoscience (Japan) and Prostate Cancer Foundation (UK).

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J.M.I. designed and did all the experiments and contributed to manuscript preparation; D.O.C. contributed to immunohistochemistry, immunoblot analysis and confocal microscopy; G.A.B. contributed to EAE experiments; M.A.T. contributed to immunoblot and in vivo assays; M.S. contributed to real-time RT-PCR; M.E.V. contributed to in vivo assays; J.R.G. provided essential reagents and intellectual support; and G.A.R. supervised the work, designed the experiments and wrote the manuscript.

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Correspondence to Gabriel A Rabinovich.

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Ilarregui, J., Croci, D., Bianco, G. et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol 10, 981–991 (2009). https://doi.org/10.1038/ni.1772

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