Abstract
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.
Highlights
The immunoglobulin superfamily (IgSF) includes over 750 members [1, 2]; at least 300 of which play an immunoregulatory inhibitory role in immune cell activation and function [3, 4]
V-domain Ig suppressor of T cell activation (VISTA) is an immunoregulatory receptor belonging to the first class of threshold homeostatic receptors, wherein it is expressed at steady state on both T cells and myeloid cells and whose expression remains high and is downregulated depending on the activation stimulus
This is in contrast to the negative feedback immune checkpoints (CTLA-4 and others) which are expressed after immune cell activation and mediate different inhibitory mechanisms to restrain further activation or responses
Summary
The immunoglobulin superfamily (IgSF) includes over 750 members [1, 2]; at least 300 of which play an immunoregulatory inhibitory role in immune cell activation and function [3, 4]. The majority of immunoregulatory receptors of promising therapeutic relevance are expressed on T cells, and set to negatively regulate T cell responses. These intriguing results present the prospect of VISTA targeting being crucial for regulating myeloid cell responses in the context of inflammatory diseases where neutrophils and monocytes play dominant roles.
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