The Leukocyte Activation Receptor CD69 Controls T Cell Differentiation through Its Interaction with Galectin-1

Abstract

CD69 is involved in immune cell homeostasis, regulating the T cell-mediated immune response through the control of Th17 cell differentiation. However, natural ligands for CD69 have not yet been described. Using recombinant fusion proteins containing the extracellular domain of CD69, we have detected the presence of a ligand(s) for CD69 on human dendritic cells (DCs). Pulldown followed by mass spectrometry analyses of CD69-binding moieties on DCs identified galectin-1 as a CD69 counterreceptor. Surface plasmon resonance and anti-CD69 blocking analyses demonstrated a direct and specific interaction between CD69 and galectin-1 that was carbohydrate dependent. Functional assays with both human and mouse T cells demonstrated the role of CD69 in the negative effect of galectin-1 on Th17 differentiation. Our findings identify CD69 and galectin-1 to be a novel regulatory receptor-ligand pair that modulates Th17 effector cell differentiation and function.

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ACKNOWLEDGMENTS

We thank R. González-Amaro, R. Lobb, M Gómez, and S. Bartlett for comments and critical reading of the manuscript.

This work was funded by grants SAF2011-25834 and ERC-2011AdG 294340-GENTRIS to F.S.-M., RECAVA RD06/0014 from the Fondo de Investigaciones Sanitarias to J.V. and F.S.-M., and INDISNET 01592006 from the Comunidad de Madrid to F.S.-M. and P.M. and by grants from the Ministerio de Economia y Competitividad (PI11/01562 to P.N.) and the Generalitat de Catalunya-AGAUR (2009SGR1409 to P.N.). The Ministry of Science and Innovation and the Pro-CNIC Foundation support CNIC.

H. de la Fuente and A. Cruz-Adalia performed experimental work and data analysis and wrote the manuscript, G. Martinez del Hoyo, D. Cibrian-Vera, and M. Ramirez-Huesca performed experiments with cells from deficient mice, P. Bonay purified Gal-1 and created some of the experimental design, D. Pérez-Hernández and J. Vázquez performed proteomic assays, P. Navarro and R. Gutierrez-Gallego performed the SPR protein interaction experiments, P. Martín designed the experiments and prepared the discussion of the data, and F. Sánchez-Madrid designed experiments, performed experimental work, analyzed the data, and wrote the manuscript.

We declare that we do not have any conflicts of interest.