Du, Chen, and You et al. explored mechanisms of LAG3-mediated T cell suppression. Optimal LAG3 inhibitory function required spatial proximity of LAG3 to TCRs (but not the CD4 co-receptor), and was facilitated by cognate peptide–MHC-II binding, resulting in disruption of intracellular CD3ε/Lck association via LAG3’s FSAL motif. To maximize the inhibitory effect of LAG3, a bridging LAG3/TCR bispecific mAb was developed to enforce LAG3/TCR proximity, which potently suppressed both CD4+ and CD8+ T cell responses and was therapeutically effective in mouse autoimmune models of multiple sclerosis, type 1 diabetes, and hepatitis.
Contributed by Katherine Turner
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 CD3_ through its intracellular FSAL motif, disrupting CD3_/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.
Author Info: (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 Hea
Author Info: (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 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. (4) 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. (5) 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. (6) 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. (7) University of Chinese Academy of Sciences, Beijing 100049, China. (8) 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. (9) Hansjrg 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. (10) 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. (11) 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. (12) Microscopy Core, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY 10016, USA. (13) Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, Zhejiang, China. (14) 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. (15) Hansjrg 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. (16) 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. (17) 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. (18) 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.
