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On the same side: VISTA and its ligands interact in cis on the cell surface

Karina Smorodinsky-Atias1, Gil Wiseglass1, Alina Artyukhova1

  • 1School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Protein Science : a Publication of the Protein Society
|December 22, 2025
PubMed

Insights

VISTA, an immune checkpoint protein, binds ligands in cis (same cell), not trans (between cells). This discovery clarifies VISTA

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • VISTA is a critical immune checkpoint protein regulating T-cell function and tolerance.
  • Understanding VISTA's binding mechanism is crucial for developing anti-tumor and autoimmune therapies.
  • Previous studies lacked clarity on VISTA's membrane orientation and ligand interaction mode.

Purpose of the Study:

  • To elucidate the binding mode and membrane orientation of VISTA.
  • To investigate whether VISTA interacts with its ligands in trans or cis.
  • To provide a framework for developing novel VISTA-targeted therapeutics.

Main Methods:

  • Cell aggregation assays to assess trans interactions.
  • MicroScale Thermophoresis (MST) and flow cytometry for soluble VISTA binding.
  • Split luciferase complementation assays for membrane-tethered VISTA interactions.
  • Cancer Genome Atlas data analysis for co-expression patterns.

Main Results:

  • VISTA does not interact with ligands in a trans manner.
  • Soluble VISTA binds ligands, but membrane-bound VISTA's orientation restricts trans interactions.
  • Membrane-tethered VISTA exhibits cis interactions with its ligands.
  • Strong VISTA and PSGL-1 co-expression correlation observed in cancer data.
  • VISTA's Ig domain likely orients towards the membrane, favoring cis interactions.

Conclusions:

  • VISTA primarily interacts with its ligands in cis, on the same cell.
  • This cis interaction suggests an intrinsic VISTA signaling pathway.
  • The findings clarify VISTA's mechanism, enabling targeted therapeutic development.
  • The study presents a novel experimental platform for VISTA drug discovery.
Keywords:
T cellVSIRcis interactionsimmune checkpointsvista

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