Transplantation/immunologyPeptides of CD200 Modulate LPS-Induced TNF-α Induction and Mortality In Vivo
Introduction
Activation of T lymphocytes by MHC-peptide complexes presented on antigen-presenting cells (APCs) is modulated by ligand binding to costimulatory and regulatory counter-ligands. Among the well-defined costimulatory molecules are CD28, CD154, CTLA4, 4-1BBL, and CD134 [1, 2, 3, 4, 5], while molecules contributing to negative signaling to T cells include PD-1 and B7-H3 [6, 7, 8]. Further regulation of activation depends upon receptor molecules encoded by other gene families, e.g., the triggering receptors expressed by myeloid cells (TREM) family [9]. We have characterized a member of the TREM family, CD200R, and shown that five members, R1-5, exist in mice, sharing structural homology with the immunoglobulin and lectin-like superfamilies, including MHC Class I molecules [10] and sialic acids [11]. The isoforms of CD200R for both mouse and human show tissue-restricted expression [12, 13] and heterogeneity of function [13, 14]. Thus, CD200R1 is expressed on macrophages/DCs and a subpopulation of T cells, and ligation by CD200 leads to association with Dok [15, 16, 17, 18], phosphorylation of ITIM-like motifs in the cytoplasmic tail, and suppression of inflammation and T cell function [9, 19]. Alternate CD200R isoforms are expressed on cells of the myeloid lineage and triggering of CD200R2/3 results in signaling via DAP-10/-12 signaling molecules [12, 15, 17, 20], producing altered myeloid cell differentiation [9, 21].
CD200 regulates inflammation in a number of tissues and model systems [18, 22, 23, 24, 25, 26, 27]. A viral homologue of CD200 has also been shown to modulate both macrophage and mast cell activation following interaction with CD200R1, as well as viral immunity to human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) [20, 28]. The onset of a generalized, often lethal, inflammatory state associated with surgical sepsis now believed to follow in part from activation of pattern recognition receptors of the innate immune system, has focused attention on mechanisms which might be brought to bear to suppress non-specific inflammation per se [29]. To date, strategies designed to suppress levels of the major inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), have had little impact in clinical disease, but in studies of inflammation and TNF-α production in a mouse model of arthritis we have shown that CD200 is a potent immunomodulator [22].
The N-terminal regions of both CD200 and CD200R are important in their mutual interaction [12, 30, 31, 32, 33]. Since the functional activity of different CD200R isoforms is not the same, characterization of CD200-derived N-terminal peptides, which may discriminate between CD200R1 or other CD200R isoforms in terms of agonist/antagonist activity, is of crucial importance. We have used responder cells from wild-type mice, or from mice lacking the gene encoding CD200R1 [34], as tools to characterize functional properties of CD200-derived peptides. We classified a peptide agonist (of CD200) as a molecule that produced the equivalent biological effect to full-length CD200Fc; an antagonist peptide in contrast is a competitive inhibitor of the biological effect produced by CD200Fc. We report use of in vitro models of allo-activated cells (induction of CTL/cytokines in mixed leukocyte cultures [MLCs]), and in vivo studies of mice receiving lethal intraperitoneal injections of the non-specific inflammatory stimulus, lipopolysaccharide (LPS), to define the sequence of CD200 peptides agonists/antagonists for CD200R1 and alternate CD200R isoforms.
Section snippets
Mice
Female C3H/HEJ, C57BL/6, and BALB/c mice were purchased from the Jackson Laboratories, Bar Harbor, ME. A CD200R1 KO mouse (BL/6 background) in which the genetic region encoding the extracellular domains of CD200R1 were deleted was generated and characterized as described elsewhere [34]. All mice were housed 5/cage and allowed food and water ad libitum. Mice were used at 8 to 12 wk of age.
Purification of CD200Fc
The mouse fusion protein (CD200Fc) encoding the extracellular domains of CD200 linked genetically to a mouse
Evidence for Agonist/Antagonist Activity of Defined CD200 Peptides in Spleen Cells Stimulated with LPS or Allogeneic Cells
Structural considerations place the most important interaction domains between CD200 and CD200R1 map to the GFCC’ face of the NH2-terminal domain of CD200R1 (Fig. 1) [30, 32, 38], a conclusion supported by studies examining suppression of CD200Fc binding to CD200R1 in FACS/ELISA by 15-mer CD200 peptides [33]. No data exist to date exploring CD200 peptide binding to alternate CD200R isoforms, and any functional effects resulting from such binding. Using spleen cells from a newly generated
Discussion
The molecular mechanisms that protect the host from invading pathogens are in turn responsible for sepsis, a response of the immune system to microbial pathogens that can, in the extreme, prove fatal. Research in the field of innate immunity has helped identify a plethora of pattern recognition receptors (PRRs) responsible for bacterial-induced activation [39]. One such family of receptors is the so-called Toll-like receptors (TLRs). The sepsis syndrome, a disease entity that causes significant
Acknowledgments
This study was supported by CIHR and CSA:CIHR grants (Canada).
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2019, Brain, Behavior, and ImmunityCitation Excerpt :CD200 is a membrane glycoprotein that is expressed ubiquitously in the CNS on neurons, endothelial cells and oligodendrocytes (Koning et al., 2009; Wright et al., 2000). Upon binding CD200R1, CD200 initiates an intra-cellular signaling cascade that results in general inhibition of myeloid cell function including pro-inflammatory cytokine responses to immune stimuli (Gorczynski et al., 2008; Jenmalm et al., 2006; Zhang et al., 2004). Indeed, disruption of CD200:CD200R1 signaling potentiates the microglial pro-inflammatory response to immune challenges (Costello et al., 2011; Denieffe et al., 2013), as well as exacerbates disease severity and progression in neuroinflammatory disease models (Hoek et al., 2000; Meuth et al., 2008; Wright et al., 2000).
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2018, Brain, Behavior, and ImmunityCitation Excerpt :CD200 is a membrane glycoprotein that is expressed ubiquitously in the CNS on neurons, endothelial cells and oligodendrocytes, while its cognate receptor CD200R is expressed almost exclusively on microglia as well as other CNS macrophages (Koning et al., 2009; Wright et al., 2000). Upon binding CD200R, CD200 initiates an intra-cellular signaling cascade that results in general inhibition of myeloid cell function including pro-inflammatory cytokine responses to immune stimuli (Gorczynski et al., 2008; Jenmalm et al., 2006; Zhang et al., 2004). Here, we explored the possibility that stress-induced disruption of CD200:C200R signaling might serve as a trigger to disinhibit microglia, thereby sensitizing the neuroinflammatory and microglial response to subsequent immune challenges.
A Truncated form of CD200 (CD200S) Expressed on Glioma Cells Prolonged Survival in a Rat Glioma Model by Induction of a Dendritic Cell-Like Phenotype in Tumor-Associated Macrophages
2016, Neoplasia (United States)Citation Excerpt :Collectively, these data suggest that CD200S not only antagonizes the CD200-CD200R interaction but also directly exhibits activating effects on CD200R+ myeloid cells including TAMs. Furthermore, it has been speculated that CDR3 or F–G loop-derived peptides with antagonistic effects on the CD200-CD200R interaction act directly on DCs, increasing both the number of CD8+ CTLs and the release of TNFα [44,45]. However, the peptides have not been shown to upregulate expression of DC markers by TAMs.
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2012, Brain, Behavior, and ImmunityCitation Excerpt :Thus activation of CD200R plays an important role in modulating microglial activation and the associated oxidative changes, supporting the evidence that CD200 acts as a neuroimmune regulatory molecule (Barclay et al., 2002). The modulatory effect of CD200Fc on microglial activation is broadly consistent with the evidence that it decreases release of inflammatory cytokines from mast cells, splenocytes and macrophages (Boudakov et al., 2007; Gorczynski et al., 2008; Jenmalm et al., 2006; Zhang et al., 2004). Similarly, CD200Fc has been shown to suppress macrophage and microglial accumulation and activation, and delay the progression of EAE (Liu et al., 2010) and these findings concur with the current observations.
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