Immunoglobulin superfamily members encoded by viruses and their multiple roles in immune evasion

Abstract

Pathogens have developed a plethora of strategies to undermine host immune defenses in order to guarantee their survival. For large DNA viruses, these immune evasion mechanisms frequently rely on the expression of genes acquired from host genomes. Horizontally transferred genes include members of the immunoglobulin superfamily, whose products constitute the most diverse group of proteins of vertebrate genomes. Their promiscuous immunoglobulin domains, which comprise the building blocks of these molecules, are involved in a large variety of functions mediated by ligand-binding interactions. The flexible structural nature of the immunoglobulin domains makes them appealing targets for viral capture due to their capacity to generate high functional diversity. Here, we present an up-to-date review of immunoglobulin superfamily gene homologs encoded by herpesviruses, poxviruses, and adenoviruses, that include CD200, CD47, Fc receptors, interleukin-1 receptor 2, interleukin-18 binding protein, CD80, carcinoembryonic antigen-related cell adhesion molecules, and signaling lymphocyte activation molecules. We discuss their distinct structural attributes, binding properties, and functions, shaped by evolutionary pressures to disarm specific immune pathways. We include several novel genes identified from extensive genome database surveys. An understanding of the properties and modes of action of these viral proteins may guide the development of novel immune-modulatory therapeutic tools.

The family of the interleukin‐1 receptors

“…The B15R soluble glycoprotein of vaccinia virus is a structural and functional homolog of sIL‐1R2, being able to efficiently bind and inhibit IL‐1β while insensitive to IL‐1Ra, thereby acting as virulence factor . The same vaccinia virus and other poxviruses (ectromelia, molluscum contagiosum, variola, monkeypox, and swinepox) also express a homolog of IL‐18BP, which can bind IL‐18 with high affinity and that is present in 2 forms, one soluble, similar to the mammalian IL‐18BP, and a long form comprising a GAG‐binding domain that can anchor the viral IL‐18BP to the membrane of host cells (, reviewed in ). That pathogenic poxviruses have developed virulence mechanisms that imply the inhibition of IL‐18 (and IL‐1) implies that these cytokines are central in the host defense against these particular pathogens.…”

A Prominent Role of the Human Cytomegalovirus UL8 Glycoprotein in Restraining Proinflammatory Cytokine Production by Myeloid Cells at Late Times during Infection

“…Mostly found in membrane proteins, they usually participate in cell-cell recognition activities, playing essential roles in immune responses, cell adhesion, and many other processes. Ig domains are also present in virally encoded proteins, although their prevalence is much lower (44,45). In HCMV, Ig domain-containing proteins have been involved in a wide range of interactions with uninfected immune cells, including with T lymphocytes and NK cells.…”

Merkel cell carcinoma expresses the immunoregulatory ligand CD200 and induces immunosuppressive macrophages and regulatory T cells

“…Because MCC frequently expresses CD200, we hypothesized that MCC tumors would associate with CD200R C immunosuppressive myeloid cells, 8,20 To confirm the presence of CD200R in the tumor microenvironment, we stained 5 fresh-frozen MCC biopsy specimens with antibodies against CD200R and the myeloid marker CD11b. Monocytes expressing CD11b and CD200R were present within tumor nests and around the tumor periphery ( Figure 2A).…”

“…CD200 is a cell surface ligand that confers immune privilege to the thymus, B cells, activated T cells, certain vascular endothelia, kidney glomeruli, placental cells, hair follicles, neurons, and various malignancies including neuroendocrine tumors, [2][3][4][5][6][7] Its receptor (CD200R) is expressed on cells of the monocyte/macrophage lineage and subsets of B and T cells. 8 Signaling by CD200 prevents normal activation of CD200R bearing myeloid cells, 9,10 eventuating in an immunosuppressive cascade that includes the induction of regulatory T cells (T regs ). 11 For example, CD200 signaling inhibits classic macrophages activation (M1 polarization) and supports an immunosuppressive M2 polarized state that secretes high levels of IL-10, thereby inducing T regs and promoting tumor growth.…”