VISTA: A Target to Manage the Innate Cytokine Storm

Front Immunol. 2021 Feb 11:11:595950. doi: 10.3389/fimmu.2020.595950. eCollection 2020.


In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.

Keywords: agonistic antibodies; cytokine storm; immune checkpoint; immunosuppression; monocyte reprogramming; myeloid; vista.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • B7 Antigens / agonists*
  • B7 Antigens / antagonists & inhibitors
  • B7 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • COVID-19 / pathology*
  • Cytokine Release Syndrome / immunology
  • Cytokine Release Syndrome / pathology
  • Cytokine Release Syndrome / prevention & control*
  • GPI-Linked Proteins / antagonists & inhibitors
  • Humans
  • Immunotherapy
  • Interferon Type I / antagonists & inhibitors
  • Lipopolysaccharide Receptors / antagonists & inhibitors
  • Lymphocyte Activation / immunology
  • Mice
  • Myeloid Cells / immunology*
  • Receptors, IgG / antagonists & inhibitors
  • SARS-CoV-2 / immunology


  • B7 Antigens
  • CD14 protein, human
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Interferon Type I
  • Lipopolysaccharide Receptors
  • Receptors, IgG
  • VSIR protein, human