Antibody Targets Immune Receptor Pairing To Regulate T Cell Response

Researchers have identified a mechanism through which Lymphocyte Activation Gene 3 (LAG-3), a key immunosuppressive receptor, suppresses T cell activity—not by ligand binding alone, but by spatial proximity to the T cell receptor (TCR) complex. The study, published June 30 in Cell, suggests that this proximity enables effective suppression of CD4+ T cells through a process known as phase separation.

The collaborative research effort included scientists from the Institute of Biophysics of the Chinese Academy of Sciences, the Grossman School of Medicine at New York University, and the School of Medicine at Zhejiang University. Their findings provide a more detailed understanding of LAG-3 function and support the development of a bispecific antibody aimed at autoimmune disease treatment.

Proximity, not ligand binding underlies receptor function

LAG-3 has been known for its role in immune checkpoint pathways, which regulate T cell activation. However, its functional mechanism has remained unclear. This study reveals that the receptor's inhibitory function depends on its ability to co-localize with the TCR within the same membrane plane—referred to as "cis-proximity."

This spatial relationship is mediated by LAG-3’s interaction with its classical ligand, Major Histocompatibility Complex class II (MHC-II), which facilitates LAG-3’s positioning next to the TCR. The resulting proximity induces a separation of membrane domains, a process that ultimately suppresses T cell activity.

This mechanism represents a departure from traditional models of immune checkpoint regulation, which emphasize ligand engagement as the principal mode of activation. In contrast, LAG-3 appears to require a context-dependent arrangement that is difficult to trigger in vivo, contributing to the limited efficacy observed in current LAG-3-based monotherapies for cancer.

A new therapeutic design for autoimmune disease

Leveraging this newly identified mechanism, the researchers developed a bispecific T cell silencer antibody, referred to as BiTS. This therapeutic simultaneously binds LAG-3 and the TCR, promoting their co-localization in pathogenic T cells that express LAG-3. In animal models of autoimmune disease, this approach demonstrated a significant therapeutic effect by selectively targeting autoreactive T cells.

This bispecific antibody offers a therapeutic strategy that exploits LAG-3’s cis-proximity-dependent activity. By creating a controlled inhibitory environment at the immune synapse, the BiTS antibody provides a precise method to modulate autoimmune responses without affecting broader immune function.

Implications for immune checkpoint research

The study introduces the concept of a “cis-proximity-dependent immune checkpoint,” distinguishing LAG-3 from other checkpoint receptors that operate through conventional ligand-receptor signaling. This insight could help explain the limited clinical success of LAG-3 monotherapies and inform the design of next-generation immunotherapies.

Although this research was conducted in animal models, the findings establish a conceptual basis for designing more selective immunomodulatory treatments. The approach may be particularly suited for autoimmune disorders, where immune suppression must be precisely targeted to avoid systemic effects.

Reference: Du J, Chen H, You J, et al. Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity. Cell. 2025. doi: 10.1016/j.cell.2025.06.004

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