CD200R1

Official Full Name

CD200 receptor 1

Organism

Homo sapiens

GeneID

131450

Background

This gene encodes a receptor for the OX-2 membrane glycoprotein. Both the receptor and substrate are cell surface glycoproteins containing two immunoglobulin-like domains. This receptor is restricted to the surfaces of myeloid lineage cells and the receptor-substrate interaction may function as a myeloid downregulatory signal. Mouse studies of a related gene suggest that this interaction may control myeloid function in a tissue-specific manner. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

Synonyms

OX2R; MOX2R; CD200R; HCRTR2;

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Detailed Information

CD200R, encoded by the CD200R1 gene, is a type I transmembrane protein belonging to the immunoglobulin superfamily. In the human genome, the CD200R1 gene encodes a receptor characterized by two extracellular Ig-like domains, a single transmembrane segment, and a relatively long cytoplasmic tail. Notably, the cytoplasmic tail lacks classical immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or activation motifs (ITAMs); instead, it recruits downstream signaling molecules via its unique terminal sequences, indicating a distinct signaling mechanism.

CD200R expression is highly restricted to myeloid cells, primarily macrophages, granulocytes, dendritic cells, and microglia, with little to no expression on adaptive immune cells such as T or B lymphocytes. This pattern strongly suggests that CD200R functions predominantly in negative regulation of innate immunity. Its only known endogenous ligand is CD200, a transmembrane glycoprotein with two Ig-like domains, broadly expressed in multiple tissue types including neurons, endothelial cells, and activated T cells. This receptor-ligand pair forms a classic immune checkpoint axis.

Biological Significance

CD200R is a critical inhibitory receptor that maintains immune homeostasis and tissue tolerance by transmitting negative signals to limit excessive myeloid cell–driven inflammation. Upon engagement with CD200, CD200R triggers intracellular events involving tyrosine phosphorylation and recruitment of adaptor proteins, ultimately leading to suppression of pro-inflammatory responses. This includes downregulation of key inflammatory mediators such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and inducible nitric oxide synthase (iNOS).

The CD200-CD200R axis is therefore considered a myeloid cell–regulatory pathway, allowing tissue cells to convey a "self" or "non-threatening" signal to infiltrating myeloid cells during homeostasis or inflammation resolution, preventing collateral tissue damage. In the central nervous system, interaction between neuronal CD200 and microglial CD200R is crucial for maintaining microglial quiescence, preventing aberrant activation, and preserving neuroimmune homeostasis.

Figure 1. CD200:CD200R1 axis. (Kotwica-Mojzych K, et al., 2021)

Certain viruses, such as human herpesvirus 8, have evolved CD200 homologs that bind CD200R with similar affinity, hijacking this inhibitory pathway to suppress host antiviral immunity and facilitate persistent infection. This highlights CD200R as a key interface in host-pathogen co-evolution.

Clinical Relevance

CD200R is clinically significant due to its roles in tumor immune evasion and autoimmune/inflammatory diseases, making it an attractive therapeutic target. Many human cancers, including leukemia, melanoma, ovarian, and colorectal cancers, exhibit abnormally high CD200 expression. Engagement of CD200R on tumor-infiltrating myeloid cells delivers potent inhibitory signals, impairing antigen presentation, pro-inflammatory functions, and promoting differentiation into M2-like macrophages or tolerogenic dendritic cells, which suppress anti-tumor T cell responses and foster an immunosuppressive microenvironment.

Therapeutic strategies aim to block CD200-CD200R interactions to reinvigorate myeloid cell function and enhance anti-tumor immunity. Monoclonal antibodies targeting CD200 or CD200R have entered early clinical trials, with the goal of enhancing immune surveillance, potentially synergizing with existing checkpoint inhibitors.

In autoimmune and inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, dysregulation of the CD200-CD200R axis contributes to pathological tissue damage. Enhancing this pathway using CD200R agonists or recombinant CD200-Fc fusion proteins could theoretically suppress overactive myeloid responses and mitigate disease progression. In neurodegenerative disorders such as Alzheimer's disease, reduced neuronal CD200 expression correlates with aberrant microglial activation, suggesting restoration of CD200R signaling may help control neuroinflammation.

Developing therapies targeting CD200R requires careful balancing of immune activation and autoimmunity risk, as well as a detailed understanding of its regulation across tissues and disease stages. Nevertheless, CD200R represents a critical myeloid immune checkpoint, opening new avenues for treating cancer and chronic inflammatory diseases.

References

Barclay AN, Wright GJ, Brooke G, Brown MH. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 2002;23(6):285–290.
Rijkers ES, de Ruiter T, Baridi A, Veninga H, Hoek RM, Meyaard L. The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Mol Immunol. 2008;45(4):1126–1135.
Kotwica-Mojzych K, Jodłowska-Jędrych B, Mojzych M. CD200:CD200R Interactions and Their Importance in Immunoregulation. Int J Mol Sci. 2021 Feb 5;22(4):1602.

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