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A pivotal role for galectin-1 in fetomaternal tolerance

Nature Medicine volume 13, pages 1450–1457 (2007)Cite this article

A Corrigendum to this article was published on 01 May 2009

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Abstract

A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1–deficient (Lgals1−/−) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)–secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.

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Figure 1: Protective role of Gal-1 during stress-challenged failing pregnancies.
Figure 2: Induction of tolerogenic uterine DCs during successful pregnancy and after treatment with recombinant Gal-1.
Figure 3: Immunoregulatory activity of Gal-1-induced tolerogenic DC during pregnancy.
Figure 4: Pivotal role of Gal-1 in fetomaternal tolerance through modulation of multiple immunoregulatory mechanisms.
Figure 5: Prevention of stress-induced fetal loss and modulation of regulatory mechanisms by adoptive transfer of Gal-1–induced tolerogenic DCs.
Figure 6: Functional cross-talk between Gal-1 and progesterone in the regulation of fetomaternal tolerance.

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Change history

  • 07 May 2009

    In the version of this article initially published, the plot labeled “Stress + Gal-1” duplicated the plot labeled “Control” for the IL-12p70 staining in Figure 2f. The corrected plots have now been provided in the HTML and PDF versions of the article. Two sentences were omitted from the section on purification of uterine DCs in the Methods. The sentences should have read: “We obtained purified DCs from uterine tissue in very low numbers. Thus, we pooled isolated cells from each group and used this cell cocktail for the isotype control staining.” The error has been corrected in the HTML and PDF versions of the article. In Figure 4f, the lanes of the western blot were merged inappropriately. The properly presented blot, in which the gel lanes have been separated to indicate that the samples were not originally run side by side, has been provided in the PDF and HTML versions of the article. The standard curve of the cytometric bead array kit used to generate the cytokine data can be found in the revised supplementary information available online.

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Acknowledgements

We thank E. Hagen, P. Moschansky and P. Busse for excellent technical assistance in generating this work. Pgr−/− mice were provided by J. Lydon (University of Texas). S.M.B., M.T., U.R.M., J.S.-B. and P.C.A. are part of the Embryo Implantation Control Network of Excellence, co-financed by the European Commission throughout the FP6 framework program Life Science, Genomics and Biotechnology for Health. S.M.B is a fellow of the Habilitation program at the Charité, University Medicine Berlin. J.M.I., M.A.T. and G.A.B. are fellows of the CONICET. A.S.O. is supported by the Turkish Higher Education Council. M.G. was supported by the German Academic Exchange Program. This work was supported by research grants from the German Research Foundation (AR232/8–1, P.C.A.), the Drs. Graute and Graute-Oppermann Foundation (P.C.A.), the Charité (P.C.A.), the Sales Foundation/CONICET Program (G.A.R.), the Mizutani Foundation for Glycoscience (G.A.R.), the Cancer Research Institute (E. Shephard Investigator; G.A.R.), the John Simon Guggenheim Memorial Foundation (G.A.R.), the Argentina National Agency for Promotion of Science and Technology (PICT 2003–05–13787; G.A.R.), the University of Buenos Aires (M091; G.A.R.) and the Association pour la Recherche contre le Cancer and Ligue contre le cancer, comité de Paris (F.P.). We are indebted to S. Cookson, B. Huppertz, D.A. Clark, H.F. Rosenberg and several anonymous reviewers for helpful feedback and constructive comments on this article.

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Author notes

  1. Juan M Ilarregui and Mareike Tometten: J.M.I. and M.T. contributed equally to this work.

Authors and Affiliations

  1. Charité, University Medicine Berlin, Biomedical Research Building, Campus Virchow, Augustenburger Platz 1, Berlin, 13353, Germany

    Sandra M Blois, Mareike Tometten, Mariana Garcia, Arif S Orsal, Rosalia Cordo-Russo, Bori Handjiski, Irene Tirado, Burghard F Klapp & Petra C Arck

  2. Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Vuelta de Obligado 2490, Buenos Aires, C1428, Argentina

    Juan M Ilarregui, Marta A Toscano, Germán A Bianco & Gabriel A Rabinovich

  3. Department of Medicine, Division of Hepatology, Gastroenterology, and Endocrinology, Charité, University Medicine Berlin, Berlin, 13353, Germany

    Peter Kobelt

  4. Departamento de Bioquímica y Biología Molecular, Unidad de Inmunología, Facultad de Medicina, Universidad de Granada, Granada, 18012, Spain

    Irene Tirado

  5. Department of Obstetrics, Placenta-Labor, Friedrich-Schiller-University Jena, Jena, 07740, Germany

    Udo R Markert

  6. Departement de Biologie du Developpement, Institut Jacques Monod, Unités Mixtes de Recherche Centre National de la Recherche 7592, Univ. Paris 6 and Paris 7, Paris, 75251, Paris, France

    Francoise Poirier

  7. Department of Medical Microbiology and Immunology, Reproductive and Tumor Immunology Research Group of the Hungarian Academy of Sciences, Pecs University Medical School, Pecs, 7643, Hungary

    Julia Szekeres-Bartho

  8. Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428, Argentina

    Gabriel A Rabinovich

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Contributions

S.M.B. developed the concept and formulated the key research questions, designed and conducted most of the experiments and wrote the manuscript. J.M.I. and M.T. designed and performed some of the experiments, M.G., A.S.O. and R.C.-R. assisted with experiments presented in Figures 1, 2, 3, 4, M.A.T. and G.A.B. contributed with essential reagents and intellectual input, P.K. assisted with histological analysis and confocal microscopy, B.H. and I.T. assisted with histological and statistical analyses, U.R.M. provided advice in the context of the Stat3 analysis, F.P. provided the Lgals1−/− mice and essential advice, B.F.K. assisted with confocal microscopy and gave input on writing the manuscript, J.S.-B. performed PIBF analysis, and G.A.R. and P.C.A. jointly supervised the work, designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Sandra M Blois, Gabriel A Rabinovich or Petra C Arck.

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Blois, S., Ilarregui, J., Tometten, M. et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med 13, 1450–1457 (2007). https://doi.org/10.1038/nm1680

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