Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse.
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.
Chen
Huan-Yuan
HY
Department of Dermatology, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
Fermin
Agnes
A
Vardhana
Santosh
S
Weng
I-Chun
IC
Lo
Kin Fong Robin
KF
Chang
En-Yuh
EY
Maverakis
Emanual
E
Yang
Ri-Yao
RY
Hsu
Daniel K
DK
Dustin
Michael L
ML
Liu
Fu-Tong
FT
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D054992:Immunological Synapses / Q000276:immunology*; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection; D020798:Two-Hybrid System Techniques
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D037502:Galectin 3; C117020:PDCD6IP protein, human; C492144:Pdcd6ip protein, mouse; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma
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