VSIG4

Official Full Name

V-set and immunoglobulin domain containing 4

Organism

Homo sapiens

GeneID

11326

Background

This gene encodes a v-set and immunoglobulin-domain containing protein that is structurally related to the B7 family of immune regulatory proteins. The encoded protein may be a negative regulator of T-cell responses. This protein is also a receptor for the complement component 3 fragments C3b and iC3b. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

Synonyms

CRIg; Z39IG;

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Detailed Information

The VSIG4 gene, officially named V-set and immunoglobulin domain containing 4, is located on human chromosome Xq12. It encodes a type I transmembrane protein belonging to the B7 family of immune regulatory proteins. The extracellular region of VSIG4 contains a V-set immunoglobulin-like domain and a C2-set immunoglobulin-like domain, enabling specific interactions with its ligands. VSIG4 expression is highly cell-type specific, predominantly found in tissue-resident macrophage subsets, including splenic marginal zone macrophages, peritoneal macrophages, and, under certain conditions, specific dendritic cell populations. This restricted expression pattern suggests that VSIG4 plays a crucial role in maintaining immune homeostasis within specialized tissue microenvironments. As a B7 family member, VSIG4 functions in the negative regulation of T cell–mediated immunity while simultaneously serving as a key regulator of the complement system, linking innate and adaptive immunity.

Biological Significance

VSIG4's biological significance stems from its dual role as an immunosuppressive receptor and a complement regulatory factor. In adaptive immunity, VSIG4 is a potent negative regulator of T cell activation. It interacts with as-yet incompletely defined T cell surface receptors to directly inhibit T cell proliferation and reduce the production of critical T cell growth factor IL-2. This inhibitory function is essential for preventing overactivation of T cells, maintaining peripheral immune tolerance, and facilitating the clearance of senescent or apoptotic cells in organs such as the spleen, thereby reducing the risk of autoimmune reactions.

Figure 1. Role of VSIG4 in the complement pathway and T cell activation. (Liu B, et al., 2023)

In innate immunity, VSIG4 functions as a receptor for complement fragments C3b and iC3b. By binding these fragments, VSIG4 competitively inhibits the formation and stabilization of the alternative pathway C3 convertase, preventing excessive complement activation. Overactivation of the complement system can damage host tissues, and VSIG4-mediated regulation is considered a key mechanism protecting tissues from complement-induced inflammatory injury. Particularly, VSIG4 facilitates "silent" clearance of complement-opsonized apoptotic cells, preventing unnecessary inflammation. Collectively, VSIG4 maintains immune homeostasis by suppressing T cell responses and regulating complement activation, forming a crucial barrier against excessive inflammation and tissue damage. Dysregulation of VSIG4 is associated with various autoimmune and inflammatory disorders.

Clinical Relevance

Clinically, VSIG4 is of interest as a potential immune checkpoint molecule and for its altered expression in inflammatory diseases and cancer. In autoimmune diseases, such as atypical hemolytic uremic syndrome, dysregulated alternative complement pathway activation is a key pathogenic mechanism. VSIG4, as an endogenous complement inhibitor, may influence disease susceptibility and severity, making it a significant disease-associated gene and potential therapeutic target.

In cancer immunology, VSIG4 expression on tumor-associated macrophages is thought to contribute to an immunosuppressive tumor microenvironment. By inhibiting T cell function, VSIG4 may facilitate tumor immune evasion, positioning it as a potential novel immune checkpoint similar to the PD-1/PD-L1 axis. Preclinical studies are exploring antagonistic antibodies targeting VSIG4 to block its immunosuppressive function, thereby "releasing" tumor-infiltrating T cells and enhancing antitumor immunity. Conversely, in chronic inflammation or tissue injury models, harnessing VSIG4's immunosuppressive and anti-inflammatory properties-e.g., via recombinant VSIG4 protein or agonists-may offer strategies for treating autoimmune diseases or preventing transplant rejection. Translating VSIG4 into a therapeutic target faces challenges, including the need for a precise understanding of its regulatory mechanisms in different pathological contexts, identification of its ligands, and assessment of potential systemic immune-related adverse effects.

References

Helmy KY, Katschke KJ Jr, Gorgani NN, et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell. 2006;124(5):915–27.
Lee KM, Najarro DH, Yoon KJ, et al. VSIG4 is a ligand of VISTA and suppresses T cell activation. Sci Immunol. 2023;8(84):eabq1249.
Liu B, Cheng L, Gao H, et al. The biology of VSIG4: Implications for the treatment of immune-mediated inflammatory diseases and cancer. Cancer Lett. 2023 Jan 28;553:215996.

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