Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse.

Journal article

We have investigated the function of endogenous galectin-3 in T cells. Galectin-3-deficient (gal3(-/-)) CD4(+) T cells secreted more IFN-gamma and IL-4 than gal3(+/+)CD4(+) T cells after T-cell receptor (TCR) engagement. Galectin-3 was recruited to the cytoplasmic side of the immunological synapse (IS) in activated T cells. In T cells stimulated on supported lipid bilayers, galectin-3 was primarily located at the peripheral supramolecular activation cluster (pSMAC). Gal3(+/+) T cells formed central SMAC on lipid bilayers less effectively and adhered to antigen-presenting cells less firmly than gal3(-/-) T cells, suggesting that galectin-3 destabilizes the IS. Galectin-3 expression was associated with lower levels of early signaling events and phosphotyrosine signals at the pSMAC. Additional data suggest that galectin-3 potentiates down-regulation of TCR in T cells. By yeast two-hybrid screening, we identified as a galectin-3-binding partner, Alix, which is known to be involved in protein transport and regulation of cell surface expression of certain receptors. Co-immunoprecipitation confirmed galectin-3-Alix association and immunofluorescence analysis demonstrated the translocation of Alix to the IS in activated T cells. We conclude that galectin-3 is an inhibitory regulator of T-cell activation and functions intracellularly by promoting TCR down-regulation, possibly through modulating Alix's function at the IS.

Authors: Chen, H; Fermin, A; Vardhana, S; Weng, I; Lo, K

• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 106
• Issue: 34
• Pages: 14496-14501
• Publication date: 2009-08-01
• DOI: 10.1073/pnas.0903497106
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Two-Hybrid System Techniques; Interleukin-4; Receptors, Antigen, T-Cell; Mice, Knockout; CD4-Positive T-Lymphocytes; Jurkat Cells; Signal Transduction; Cell Cycle Proteins; Mice; Mice, Inbred C57BL; Immunoprecipitation; Cell Line; Interferon-gamma; Transfection; Lymphocyte Activation; Humans; Endosomal Sorting Complexes Required for Transport; Protein Binding; Animals; Immunological Synapses; Galectin 3; Calcium-Binding Proteins; Immunoblotting