VISTA is an activating receptor in human monocytes

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• V-domain Ig suppressor of T cell activation (VISTA) is primarily known as an inhibitory protein limiting immune responses.
• The specific effects of VISTA agonism on immune cell biology, independent of other activation signals, remain largely unexplored.

Purpose of the Study:

• To investigate the effects of novel VISTA-targeting antibodies on human immune cells.
• To elucidate the mechanisms and consequences of VISTA agonism in monocytes.
• To identify novel regulators of VISTA interactions with monocytic cells.

Main Methods:

• scRNA/CITE-seq analysis of human peripheral blood mononuclear cells treated with novel VISTA antibodies.
• Characterization of Fc-functional VISTA agonism.
• Utilizing pentameric VISTA to identify interaction partners.

Main Results:

• Two novel VISTA antibodies demonstrated Fc-functional agonism, inducing transcriptional and functional changes in monocytes indicative of activation.
• Syndecan-2 and genes involved in heparan sulfate proteoglycan synthesis were identified as novel regulators of VISTA interactions with monocytic cells.
• Evidence for bidirectional signaling between VISTA and monocytic cells was established.

Conclusions:

• VISTA agonism, mediated by specific antibodies, can activate myeloid cells, challenging its purely inhibitory role.
• Syndecan-2 emerges as a significant factor in modulating VISTA-cell interactions.
• This research provides a foundation for understanding VISTA's complex role in myeloid cell biology and immune regulation.