Galectin-9 binding to HLA-DR in dendritic cells controls immune synapse formation and T cell proliferation

To initiate T cell-mediated immunity, dendritic cells (DCs) present antigens to T cells through the establishment of an immune synapse (IS). While events behind IS formation in T cells are well understood, the organization of IS components at the DC membrane remains ill-defined. Galectins modulate immune responses via glycan-(in)dependent interactions but the molecular mechanisms underlying their function in DC-mediated T cell activation, are poorly described. Here, we demonstrate that intracellular galectin-9 (gal9) in DCs is required for CD4<sup>+</sup> T cell activation through its interaction with the HLA-DR alpha- and beta- cytoplasmic domains, as supported by coimmunoprecipitation, mass spectrometry, and NMR analyses. Live-cell imaging revealed gal9-depleted DCs fail to establish stable ISs with T cells, reducing T cell activation and proliferation. Notably, HLA-DR membrane lateral mobility and recruitment to the IS was diminished in DCs lacking gal9. Conditional gal9 knockout in DCs led to enhanced tumor growth in vivo, underscoring a role for gal9 in T cell-dependent antitumor immunity. Collectively, this study reports gal9-mediated HLA-DR organization at the DC synapse, uncovering a mechanism through which intracellular galectins coordinate immune receptor positioning to enhance CD4<sup>+</sup> T cell activation.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-12-08
DOI
https://doi.org/10.1073/pnas.2501381122
Primary Topic
Galectins and Cancer Biology
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Galectin-9 binding to HLA-DR in dendritic cells controls immune synapse formation and T cell proliferation

Martijn Verdoes, René Classens, Mayukha Bathini, Andrea Rodgers Furones et al.
Proceedings of the National Academy of Sciences
Galectins and Cancer Biology
article

Galectin-9 binding to HLA-DR in dendritic cells controls immune synapse formation and T cell proliferation

Martijn Verdoes, René Classens, Mayukha Bathini, Andrea Rodgers Furones, Rik G.H. Lindeboom, Ana Ardá, Zacharias Wijfjes, Annemiek B. van Spriel, Lona J. Kroese, Laia Querol Cano, Jesús Jiménez‐Barbero, Sandra Delgado, Mirane Florencio-Zabaleta, Guido van Mierlo, Kristina Fedorova, Thijs Brands, Guusje van Gameren
article en

Abstract

To initiate T cell-mediated immunity, dendritic cells (DCs) present antigens to T cells through the establishment of an immune synapse (IS). While events behind IS formation in T cells are well understood, the organization of IS components at the DC membrane remains ill-defined. Galectins modulate immune responses via glycan-(in)dependent interactions but the molecular mechanisms underlying their function in DC-mediated T cell activation, are poorly described. Here, we demonstrate that intracellular galectin-9 (gal9) in DCs is required for CD4<sup>+</sup> T cell activation through its interaction with the HLA-DR alpha- and beta- cytoplasmic domains, as supported by coimmunoprecipitation, mass spectrometry, and NMR analyses. Live-cell imaging revealed gal9-depleted DCs fail to establish stable ISs with T cells, reducing T cell activation and proliferation. Notably, HLA-DR membrane lateral mobility and recruitment to the IS was diminished in DCs lacking gal9. Conditional gal9 knockout in DCs led to enhanced tumor growth in vivo, underscoring a role for gal9 in T cell-dependent antitumor immunity. Collectively, this study reports gal9-mediated HLA-DR organization at the DC synapse, uncovering a mechanism through which intracellular galectins coordinate immune receptor positioning to enhance CD4<sup>+</sup> T cell activation.

Proceedings of the National Academy of SciencesVol. 122(50)
Ikerbasque (ES), Radboud University Nijmegen (NL), University of the Basque Country (ES), Radboud University Medical Center (NL), The Netherlands Cancer Institute (NL), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Oncode Institute (NL), CIC bioGUNE (ES), Cancer Genomics Centre (NL)
Cancer Research Institute, Ministerie van Volksgezondheid, Welzijn en Sport, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Radboud Universitair Medisch Centrum, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Openalex Percentile: Top 55%
Galectins and Cancer Biology
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.