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  3. Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity

  • Cell. 2025 Jul 24;188(15):4025-4042.e20. doi: 10.1016/j.cell.2025.06.004.
Jasper Du 1,  Hui Chen 2,  Jia You 1,  Wei Hu 3,  Jia Liu 1,  Qiao Lu 1,  Yong Zhang 4,  Jie Gao 5,  Meng-Ju Lin 6,  Connor James Ryan Foster 1,  Eric Rao 1,  Michael Cammer 7,  Weiwei Yin 8,  Shohei Koide 9,  Catherine Pei-Ju Lu 6,  Wei Chen 10,  Jizhong Lou 11,  Jun Wang 12
Affiliations

Affiliations

  • 1 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • 2 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Department of Cardiology and Department of Cell Biology, The Second Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, Zhejiang, China; Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Department of Cardiology and Department of Cell Biology, The Second Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, Zhejiang, China.
  • 6 Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 7 Microscopy Core, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 8 Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, Zhejiang, China.
  • 9 The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 10 Department of Cardiology and Department of Cell Biology, The Second Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, Zhejiang, China. Electronic address: jackweichen@zju.edu.cn.
  • 11 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jlou@ibp.ac.cn.
  • 12 Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA. Electronic address: jun.wang@nyulangone.org.
PMID: 40592325 DOI: 10.1016/j.cell.2025.06.004
Abstract

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Keywords

CD3ε; LAG-3; Lck; MHC class II; TCR; autoimmunity; bispecific T cell silencer; cis-proximity; condensation; immunotherapy.

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