Cells of the innate and adaptive immune systems contain a variety of transmembrane surface receptors that initiate or inhibit pro-inflammatory signaling. Inhibitory receptors dampen the amplitude and limit the duration of the inflammatory response. These receptors are activated by interaction with their ligands, which are also, commonly, cell surface proteins. We study CD200R1, a 301 amino acid transmembrane glycoprotein expressed on the surface of myeloid and glial cells. CD200R1 interacts with CD200, which is expressed on the surface of neurons, epithelial cells, endothelial cells, and lymphocytes. CD200R1 has a 67 amino acid intracellular domain with a unique inhibitory tyrosine motif. Using CD200R1 KO mice generated by our laboratory, we have found that Herpes Simplex Virus-1 (HSV-1) requires CD200R1 for successful viral infection of the brain, either via support of viral replication or by suppression of host defenses [Link to publication]. Understanding this process is a major goal of this project.
We have identified a surprising pro-inflammatory role for CD200R1 in the absence of CD200. In CD200R1 KO macrophages, the generation of IL-6 and CCL5 (Rantes) in response to ligands for TLR2 (but not TLR4) was blunted by 80% compared to WT cells [Link to publication]. Our goal is to determine the molecular mechanisms by which CD200R1 can function both as an inhibitory receptor when activated by CD200, but also support or “license” pro-inflammatory signaling in the absence of this ligand. We are testing the hypothesis that the association of the cytoplasmic tail of CD200R1 with different proteins controls these functions. We are employing SILAC, mass spectrometry, and crosslinking approaches to identify these proteins, molecular imaging approaches to confirm the interactions, and biological approaches to support our results.