CD200 Immune Checkpoint Molecule for Drug Development
Overview of CD200
CD200, formerly known as OX-2, is a transmembrane glycoprotein and a member of the immunoglobulin (Ig) supergene family. CD200 has two Ig-like domains, a single transmembrane region and a short cytoplasmic tail with no known signaling motifs, suggesting that CD200 does not induce signaling in the cells expressing it. CD200 is highly conserved, with 74% amino acid homology between the human and murine orthologs. Although discrepancies on CD200 expression might be related to detection techniques and/or the activation state of the cells, it is now well accepted that CD200 is broadly distributed on cells from both hematopoietic and nonhematopoietic origin and is conserved between humans and rodents.
The structure of the CD200 receptors shares similarities with CD200, both containing two Ig superfamily extracellular domains and a single transmembrane region. In contrast with CD200, the receptors have a longer cytoplasmic domain with signaling capacity.
Fig.1 CD200 and CD200 receptor expression in the airways. (Lauzon-Joset, 2019)
The human, rat, and murine CD200 receptor families are emerging as a paired inhibitory and activating receptor system with CD200R acting as an inhibitory receptor. The molecular mechanism by which CD200R modulates functional activity has been characterized in mouse mast cells. Unlike most immune inhibitor receptors, the cytoplasmic tail of CD200R lacks a classical ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence but contains a novel phosphotyrosine binding motif NPXY. Following ligation by CD200, CD200R is phosphorylated and binds SHIP via intermediate adaptor proteins. This results in the recruitment of the GTPase activator RasGAP and inhibition of the Ras/MAPK signal transduction pathways. Activation of ERK, JNK, and p38 MAPK pathways is inhibited by CD200R engagement, resulting in inhibition of degranulation and cytokine production in mast cells.
The ligation of CD200 with its receptor, CD200R, imparts a multipronged immunosuppressive signal, potently inhibiting T-cell immune responses and natural killer (NK) cytotoxic activity, promoting macrophage secretion of indoleamine-2,3 dioxygenase (IDO), an immunosuppressive tryptophan-catabolizing enzyme, and triggering regulatory T cell (Treg) expansion. The immune checkpoint function of CD200 on dendritic cells and lymphoid effector cells modulates the activation threshold of inflammatory immune responses and contributes to the maintenance of self-tolerance.
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