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The main role of the immune system is to protect the organism against damage by ensuring an adequate response against various pathogens such as viruses, fungi, bacteria, parasites, environmental harm stimuli including allergens, haptens, and also from damage that may result from inappropriate immune system activation. Therefore, the immune system has to comprise mechanisms that maintain homeostasis, including both activatory and inhibitory mechanisms. CD200 and CD200R molecules are involved in the downregulation of myeloid and lymphoid cells. They provide immunomodulatory effects, are able to induce immune tolerance, regulate all differentiation, adhesion, and chemotaxis of various cell populations, mediators and cytokines release.
CD200/CD200R-signaling increases the threshold for immune activation and is known to be vital for restraining inflammatory responses. On the contrary, CD200 expression on tumor cells is a marker for disease progression, suggesting a role in suppression of anti-tumor responses. CD200/CD200R1 signaling has been implicated in a number of immune-related diseases such as allergic disorders, infection, arthritis, transplantation, and autoimmune disorders such as multiple sclerosis and systemic lupus erythematosus.
The structures of CD200 and CD200R
CD200 and CD200R, type I transmembrane‑anchored glycoproteins, are structurally similar to immunoglobulins. Their extracellular N2 terminal domain contains both C‑type and V‑type regions. CD200 and CD200R are identical in their extracellular parts, while they differ in their cytosolic COOH tails. Compared to CD200R, CD200 has a minimal intracellular region which lacks the capacity to transmit either activatory or inhibitory signal, but the CD200R upon ligation is capable of downregulating the exaggerated activity of the immune system to protect the organism from harm caused by its overactivity.
Gene cloning is used independently by two groups to identify a molecule (CD200R1) recognized by an antibody which blocks CD200 binding to macrophages. CD200R1 also binds a soluble chimeric protein in which the extracellular domains of CD200 are linked with the mouse immunoglobulin Fc region. Like CD200, CD200R1 contains two IgSF domains, but the longer cytoplasmic domain has a potential signaling capacity. Using a variety of molecular techniques, other members of the CD200R family are identified and referred to as CD200R (2-5) or CD200RLa-d (for CD200R-like). Only CD200R1 expresses the long cytoplasmic tail, with alternate CD200Rs containing a short cytoplasmic region and a positively charged lysine residue in the transmembrane region.
CD200/CD200R: an immunological check point
CD200 is expressed on thymocytes, activated T cells, B cells, dendritic cells (DCs), hair follicular cells, vascular endothelial cells, in the central nervous system and in the retina. CD200 has a short intracellular tail devoid of any known signaling motifs and functions as a ligand for CD200R. In contrast to the broad distribution of CD200, the CD200R expression is much more restricted. The CD200R intracellular domain is devoid of the classical immunoreceptor tyrosine-based inhibition motif (ITIM) present in most immune inhibitory receptors but it does have three tyrosine residues that can be phosphorylated, one of which is embedded in an NPXY motif. Triggering of CD200R, depending on the cell type, inhibits degranulation of mast cells and/or cytokine production. The inhibition is thought to be mediated by the recruitment of Dok2 and RasGAP to the intracellular domain of CD200R (Figure 1). Stimulation of CD200R on bone marrow-derived mast cells in vitro inhibits activation of Ras and its downstream target ERK as well as p38 and JNK.
Figure 1. The expression pattern of CD200 and CD200R
Regulation of the anti-tumor response by tumor-expressed CD200
Direct inhibition CD200/CD200R signaling was shown for NK cells where CD200-expressing targets inhibit NK cell cytotoxic activity and IFNγ production. Several in vitro studies show an inhibitory effect of CD200/CD200R signaling on the activity of T cells. For example, CD200-positive chronic lymphocytic leukemia (CLL) cells suppress pro-inflammatory cytokine production and tumor cell lysis in mixed lymphocyte cultures, which can be reversed by blocking CD200 antibodies. Similarly, CD200 blocking antibodies increase IL-2 and IFNγ production in allogeneic mixed lymphocyte reactions of T cells and dendritic cells (DCs) with melanoma and ovarian cancer cell lines. Knock down of CD200 in melanoma cells also results in enhanced T cell responses in vitro. Indirect inhibition of T cells by CD200R was initially shown in antigen-specific T cell stimulations in vitro, where CD200R-block on monocytes but not on T cells was essential for inhibition. These results were reproduced in a tumor model where CD200-expressing plasmacytoma cells are unable to inhibit cytotoxic T lymphocytes activity directly, while influence T cell function by changing the cytokine profile of tumor-associated macrophages. In brief, CD200 can trigger CD200R inhibitory signaling both on CD200R expressing NK cells and myeloid cells (Figure 2).
Figure 2. CD200 expressed on tumor, stromal or activated immune cells triggers CD200R on antigen presenting cells.
Manipulation of CD200R signaling as a therapeutic option in cancer
Manipulation of CD200–CD200R signaling both in vivo and in vitro was extensively studied, aiming at improvement of the immune response in autoimmune and tumor models. The only currently ongoing therapeutic trial is based on the use of CD200 blocking antibodies in B-CLL patients. Importantly, recent studies now indicate that this treatment could be possibly extended to CD200-negative tumors. However, an issue of concern is the impact of CD200 blockade on inflammation that may stimulate tumor growth or progression.
Another matter to consider is the possible side effects of CD200R checkpoint blockade. In similar therapies like anti-CTLA-4 and anti-PD-1 severe side effects, collectively described as immune-related adverse events, are common. Unlike CTLA4-deficient mice, CD200 deficient mice do not have any apparent phenotype and develop autoimmune conditions only when challenged. This suggests that manipulation of this pathway may be safer and result in less autoimmune problems. However, an issue of concern is the response to microbial infections in treated individuals. Since Cd200-/- mice have increased inflammation and immune pathology after viral and bacterial infection, CD200/CD200R-blockade may result in similar problems when encountering common pathogens.
All studies to date confirm that CD200/CD200R interaction promotes inhibitory activities of the immune system. These molecules play an irreplaceable role in maintaining homeostasis, suppressing inflammatory response to both internal stimuli (hypoxia, oxygen radicals, tissue damage, etc.) and external stimuli (pathogens, allergens, etc.). Current studies of CD200 and CD200R are aimed at investigating their therapeutic potential for the treatment of diseases associated with increased immune system activity.
In the context of anti-tumor responses, CD200/CD200R inhibitory signaling can modulate inflammation and thereby stimulate anti-tumor responses. However, increased inflammation can also have the opposite effect by stimulating tumor growth or progression. The mechanism of CD200/CD200R signaling pathway is still uncertain. While it seems that multiple CD200-and CD200R-expressing cell populations are involved in the inhibitory immune effects. The impact of CD200/CD200R signaling is most probably not limited to the local site of tumor growth but may systemically affect tolerance for tumor antigens. Therefore, the CD200R blockade may be a highly effective anti-cancer treatment even in the case of CD200-negative tumors.
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