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Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death

Abstract

Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17–producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17–differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1–induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1–deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.

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Figure 1: Differential susceptibility of human TH1 and TH2 cells to galectin-1-induced cell death.
Figure 2: Differential binding of galectin-1 to human TH1 and TH2 cells.
Figure 3: Differential glycosylation of human TH1 and TH2 cells selectively regulates susceptibility to galectin-1-induced cell death.
Figure 4: Glycosylation profiles and susceptibility to galectin-1-induced death of in vivo–generated TH1 and TH2 cells.
Figure 5: Critical function for galectin-1 in the negative regulation of TH1 responses.
Figure 6: TH-17-differentiated cells share a common glycan motif with TH1 cells, which can be targeted by galectin-1.
Figure 7: Galectin-1 deficiency results in enhanced susceptibility to autoimmune neuroinflammation with increased TH-17 and TH1 bias in vivo. (a) Disease progression of wild-type and Lgals1−/− mice (129/Sv) immunized with MOG(35–55).
Figure 8: Galectin-1 limits the frequency of MOG(35–55)-reactive IL-17- and IFN-γ-producing CD4+ T cells in vivo.

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Acknowledgements

We thank H. Rosenberg for critical reading of the manuscript; J. Hirabayashi, K.I Kasai and F.T. Liu for plasmids; C. Stanley, L. Campagna, M. Barboza, M. Vermeulen and the staff of the Animal Facility (Facultad de Ciencias Exactas y Naturales, University of Buenos Aires) for technical assistance; and G. Vasta, L. Steinman, M. Lenardo, L. Glimcher, R. Schreiber, C. Weaver, N. Rubinstein, L. Fainboim and J. Geffner for comments or advice. Rabbit antiserum to ST6Gal1 was from K. Colley (University of Illinois, Chicago) and endotoxin-free SEA was from M. Doenhoff (University of Wales). Supported by the Cancer Research Institute (G.A.R.), the Mizutani Foundation for Glycoscience (G.A.R.), the Sales Foundation (G.A.R.), the National Agency for Promotion of Science and Technology (G.A.R.), the Wellcome Trust (G.A.R. and E.M.R.), the University of Buenos Aires (G.A.R.), the Bunge & Born Foundation (G.A.R.), the Fiorini Foundation (G.A.R.), the National Institutes of Health (L.G.B. and J.D.H.), Ligue Contre le Cancer (F.P.), the John Simon Guggenheim Memorial Foundation (G.A.R.) and The National Research Council for Scientific and Technical Investigations (G.A.R. and N.W.Z.).

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M.A.T. designed and did experiments and contributed to manuscript preparation; G.A.B. and J.M.I. designed and did experiments; D.O.C. assisted with histological data; J.C. assisted with EAE experiments; F.P. provided Lgals1−/− mice and advice; N.W.Z., J.D.H., L.G.B. and E.M.R. contributed reagents and to the design of experiments and writing of the manuscript; and G.A.R. conceptualized and supervised the work, designed the experiments and wrote the manuscript.

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Correspondence to Gabriel A Rabinovich.

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Toscano, M., Bianco, G., Ilarregui, J. et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 8, 825–834 (2007). https://doi.org/10.1038/ni1482

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