About this Journal Submit a Manuscript Table of Contents
ISRN Immunology
Volume 2012 (2012), Article ID 682168, 18 pages
http://dx.doi.org/10.5402/2012/682168
Review Article

CD200:CD200R-Mediated Regulation of Immunity

Departments of Surgery and Immunology, University Health Network and The Toronto Hospital, Toronto, ON, Canada M5G 1L7

Received 22 October 2012; Accepted 14 November 2012

Academic Editors: R. Orentas and P. Puccetti

Copyright © 2012 Reginald M. Gorczynski. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. N. Barclay and H. A. Ward, “Purification and chemical characterisation of membrane glycoproteins from rat thymocytes and brain, recognised by monoclonal antibody MRC OX2,” European Journal of Biochemistry, vol. 129, no. 2, pp. 447–458, 1982. View at Scopus
  2. W. R. McMaster and A. F. Williams, “Monoclonal antibodies to Ia antigens from rat thymus: cross reactions with mouse and human and use in purification of rat Ia glycoproteins,” Immunological Reviews, vol. 47, pp. 117–137, 1979. View at Scopus
  3. A. D. Dick, C. Broderick, J. V. Forrester, and G. J. Wright, “Distribution of OX2 antigen and OX2 receptor within retina,” Investigative Ophthalmology and Visual Science, vol. 42, no. 1, pp. 170–176, 2001. View at Scopus
  4. M. D. Rosenblum, E. B. Olasz, K. B. Yancey et al., “Expression of CD200 on epithelial cells of the murine hair follicle: a role in tissue-specific immune tolerance?” Journal of Investigative Dermatology, vol. 123, no. 5, pp. 880–887, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. D. A. Clark, A. Keil, Z. Chen, U. Markert, J. Manuel, and R. M. Gorczynski, “Placental trophoblast from successful human pregnancies expresses the tolerance signaling molecule, CD200 (OX-2),” American Journal of Reproductive Immunology, vol. 50, no. 3, pp. 187–195, 2003. View at Publisher · View at Google Scholar · View at Scopus
  6. G. J. Wright, H. Cherwinski, M. Foster-Cuevas et al., “Characterization of the CD200 receptor family in mice and humans and their interactions with CD200,” The Journal of Immunology, vol. 171, no. 6, pp. 3034–3046, 2003. View at Scopus
  7. R. Gorczynski, Z. Q. Chen, Y. Kai, L. Lee, S. Wong, and P. A. Marsden, “CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules,” The Journal of Immunology, vol. 172, no. 12, pp. 7744–7749, 2004. View at Scopus
  8. D. Hatherley, H. M. Cherwinski, M. Moshref, and A. N. Barclay, “Recombinant CD200 protein does not bind activating proteins closely related to CD200 receptor,” The Journal of Immunology, vol. 175, no. 4, pp. 2469–2474, 2005. View at Scopus
  9. A. E. Morelli and A. W. Thomson, “Tolerogenic dendritic cells and the quest for transplant tolerance,” Nature Reviews Immunology, vol. 7, no. 8, pp. 610–621, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Gordon, “Alternative activation of macrophages,” Nature Reviews Immunology, vol. 3, pp. 23–35, 2003. View at Publisher · View at Google Scholar
  11. Z. S. Nagy, J. Ross, H. Cheng, S. M. Stepkowski, and R. A. Kirken, “Regulation of lymphoid cell apoptosis by Jaks and Stats,” Critical Reviews in Immunology, vol. 24, no. 2, pp. 87–110, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. J. V. Ravetch and L. L. Lanier, “Immune inhibitory receptors,” Science, vol. 290, no. 5489, pp. 84–89, 2000. View at Publisher · View at Google Scholar · View at Scopus
  13. P. R. Taylor, L. Martinez-Pomares, M. Stacey, H. H. Lin, G. D. Brown, and S. Gordon, “Macrophage receptors and immune recognition,” Annual Review of Immunology, vol. 23, pp. 901–944, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Lucas, L. Daniel, E. Tomasello, et al., “Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice,” European Journal of Immunology, vol. 32, no. 9, pp. 2653–2663, 2002.
  15. P. A. Oldenborg, “Role of CD47 in erythroid cells and in autoimmunity,” Leukemia and Lymphoma, vol. 45, no. 7, pp. 1319–1327, 2004. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Colonna, “TREMs in the immune system and beyond,” Nature Reviews Immunology, vol. 3, no. 6, pp. 445–453, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. G. J. Wright, M. J. Puklavec, A. C. Willis et al., “Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function,” Immunity, vol. 13, no. 2, pp. 233–242, 2000. View at Scopus
  18. A. Kharitonenkov, Z. Chen, I. Sures, H. Wang, J. Schilling, and A. Ullrich, “A family of proteins that inhibit signalling through tyrosine kinase receptors,” Nature, vol. 386, no. 6621, pp. 181–186, 1997. View at Publisher · View at Google Scholar · View at Scopus
  19. F. Borriello, J. Lederer, S. Scott, and A. H. Sharpe, “MRC OX-2 defines a novel T cell costimulatory pathway,” The Journal of Immunology, vol. 158, no. 10, pp. 4548–4554, 1997. View at Scopus
  20. R. M. Gorczynski, M. S. Cattral, Z. G. Chen et al., “An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant that prolongs allo- and xenograft survival,” The Journal of Immunology, vol. 163, no. 3, pp. 1654–1660, 1999. View at Scopus
  21. R. M. Gorczynski, Z. Chen, Y. Kai, and J. Lei, “Evidence for persistent expression of OX2 as a necessary component of prolonged renal allograft survival following portal vein immunization,” Clinical Immunology, vol. 97, no. 1, pp. 69–78, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. D. Hatherley and A. N. Barclay, “The CD200 and CD200 receptor cell surface proteins interact through their N-terminal immunoglobulin-like domains,” European Journal of Immunology, vol. 34, no. 6, pp. 1688–1694, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. P. A. van der Merwe and A. N. Barclay, “Analysis of cell-adhesion molecule interactions using surface plasmon resonance,” Current Opinion in Immunology, vol. 8, no. 2, pp. 257–261, 1996. View at Publisher · View at Google Scholar · View at Scopus
  24. R. Gorczynski, I. Boudakov, and I. Khatri, “Peptides of CD200 modulate LPS-Induced TNF-alpha induction and mortality in vivo,” Journal of Surgical Research, vol. 145, no. 1, pp. 87–96, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. R. M. Gorczynski, I. Boudakov, and I. Khatri, “A comparison of the biological properties of small molecular weight agonists and antagonists of CD200:CD200R interactions,” Medicinal Chemistry, vol. 4, no. 6, pp. 624–631, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. J. A. Hamerman, N. K. Tchao, C. A. Lowell, and L. L. Lanier, “Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12,” Nature Immunology, vol. 6, no. 6, pp. 579–586, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. H. Kubagawa, C. C. Chen, L. H. Ho et al., “Biochemical nature and cellular distribution of the paired immunoglobulin-like receptors, PIR-A and PIR-B,” Journal of Experimental Medicine, vol. 189, no. 2, pp. 309–317, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. J. Samaridis and M. Colonna, “Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways,” European Journal of Immunology, vol. 27, no. 3, pp. 660–665, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Dietrich, M. Cella, M. Seiffert, H. J. Bühring, and M. Colonna, “Cutting edge: signal-regulatory protein β1 is a DAP12-associated activating receptor expressed in myeloid cells,” The Journal of Immunology, vol. 164, no. 1, pp. 9–12, 2000. View at Scopus
  30. S. Zhang and J. H. Phillips, “Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation,” Journal of Leukocyte Biology, vol. 79, no. 2, pp. 363–368, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. S. L. Zhang, H. Cherwinski, J. D. Sedgwick, and J. H. Phillips, “Molecular mechanisms of CD200 inhibition of mast cell activation,” The Journal of Immunology, vol. 173, no. 11, pp. 6786–6793, 2004. View at Scopus
  32. R. Mihrshahi and M. H. Brown, “Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling,” The Journal of Immunology, vol. 185, no. 12, pp. 7216–7222, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. R. M. Gorczynski, “Transplant tolerance modifying antibody, to CD200 receptor, but not CD200, alters cytokine production profile from stimulated macrophages,” European Journal of Immunology, vol. 31, no. 8, pp. 2331–2337, 2001. View at Publisher · View at Google Scholar
  34. I. Boudakov, P. Chang, and R. M. Gorczynski, “Mechanisms involved in suppression induced by CD200:CD200R interaction,” Recent Research Developments in Immunology, vol. 7, pp. 9–24, 2005.
  35. R. M. Gorczynski, I. Khatri, L. Lee, and I. Boudakov, “An interaction between CD200 and monoclonal antibody agonists to CD200R2 in development of dendritic cells that preferentially induce populations of CD4+CD25+ T regulatory cells,” The Journal of Immunology, vol. 180, no. 9, pp. 5946–5955, 2008. View at Scopus
  36. D. Voehringer, D. B. Rosen, L. L. Lanier, and R. M. Locksley, “CD200 receptor family members represent novel DAP12-associated activating receptors on basophils and mast cells,” The Journal of Biological Chemistry, vol. 279, no. 52, pp. 54117–54123, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. I. Khatri, I. Boudakov, B. Lamptey, et al., “Structural and functional consequences of switching carboxy terminal domains in mouse CD200 receptors,” Open Journal of Immunology. In press.
  38. A. L. Mellor and D. H. Munn, “IDO expression by dendritic cells: tolerance and tryptophan catabolism,” Nature Reviews Immunology, vol. 4, no. 10, pp. 762–774, 2004. View at Publisher · View at Google Scholar · View at Scopus
  39. F. Fallarino, C. Asselin-Paturel, C. Vacca et al., “Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement,” The Journal of Immunology, vol. 173, no. 6, pp. 3748–3754, 2004. View at Scopus
  40. M. C. Jenmalm, H. Cherwinski, E. P. Bowman, J. H. Phillips, and J. D. Sedgwick, “Regulation of myeloid cell function through the CD200 receptor,” The Journal of Immunology, vol. 176, no. 1, pp. 191–199, 2006. View at Scopus
  41. E. S. K. Rijkers, T. de Ruiter, A. Baridi, H. Veninga, R. M. Hoek, and L. Meyaard, “The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes,” Molecular Immunology, vol. 45, no. 4, pp. 1126–1135, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. L. Gorczynski, Z. Chen, J. Hu et al., “Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells,” The Journal of Immunology, vol. 162, no. 2, pp. 774–781, 1999. View at Scopus
  43. K. Sato, K. Eizumi, T. Fukaya et al., “Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease,” Blood, vol. 113, no. 19, pp. 4780–4789, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. M. D. Rosenblum, E. Olasz, J. E. Woodliff et al., “CD200 is a novel p53-target gene involved in apoptosis-associated immune tolerance,” Blood, vol. 103, no. 7, pp. 2691–2698, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. R. H. Hoek, S. R. Ruuls, C. A. Murphy et al., “Down-regulation of the macrophage lineage through interaction with OX2 (CD200),” Science, vol. 290, no. 5497, pp. 1768–1771, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. M. B. Graeber, F. López-Redondo, E. Ikoma et al., “The microglia/macrophage response in the neonatal rat facial nucleus following axotomy,” Brain Research, vol. 813, no. 2, pp. 241–253, 1998. View at Publisher · View at Google Scholar · View at Scopus
  47. I. K. Campbell, J. A. Hamilton, and I. P. Wicks, “Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis,” European Journal of Immunology, vol. 30, no. 6, pp. 1568–1575, 2000.
  48. M. Robertson, L. P. Erwig, J. Liversidge, J. V. Forrester, A. J. Rees, and A. D. Dick, “Retinal micro-environment determines both resident and infiltrating macrophage function during experimental autoimmune uveoretinitis (EAU),” Investigative Ophthalmology & Visual Science, vol. 44, pp. 3034–3041, 2002.
  49. C. Broderick, R. M. Hoek, J. V. Forrester, J. Liversidge, J. D. Sedgwick, and A. D. Dick, “Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis,” The American Journal of Pathology, vol. 161, no. 5, pp. 1669–1677, 2002. View at Scopus
  50. E. S. K. Rijkers, T. de Ruiter, M. Buitenhuis, H. Veninga, R. M. Hoek, and L. Meyaard, “Ligation of CD200R by CD200 is not required for normal murine myelopoiesis,” European Journal of Haematology, vol. 79, no. 5, pp. 410–416, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. R. M. Gorczynski, Z. Chen, I. Khatri, and K. Yu, “sCD200 isoforms present in mice receiving skin allografts cause immunosuppression in vitro and induce Tregs,” The Journal of Immunology. In press.
  52. R. M. Gorczynski, D. A. Clark, N. Erin, and I. Khatri, “Role of CD200 expression in regulation of metastasis of EMT6 tumor cells in mice,” Breast Cancer Research and Treatment, vol. 130, no. 1, pp. 49–60, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. W. G. Cui, E. Cuartas, J. Ke et al., “CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 36, pp. 14436–14441, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. L. Lee, O. Kos, and R. M. Gorczynski, “Altered expression of mRNAs implicated in osteogenesis under conditions of simulated microgravity is regulated by CD200:CD200R,” Acta Astronautica, vol. 63, no. 11-12, pp. 1326–1336, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. L. Lee, J. Liu, J. Manuel, and R. M. Gorczynski, “A role for the immunomodulatory molecules CD200 and CD200R in regulating bone formation,” Immunology Letters, vol. 105, no. 2, pp. 150–158, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. O. Kos, L. Lee, and R. M. Gorczynski, “CD200:CD200R interactions regulate osteoblastogenesis and osteoclastogenesis in space,” Journal of Gravitational Physiology, vol. 15, no. 1, pp. 109–111, 2008.
  57. R. J. Snelgrove, J. Goulding, A. M. Didierlaurent et al., “A critical function for CD200 in lung immune homeostasis and the severity of influenza infection,” Nature Immunology, vol. 9, no. 9, pp. 1074–1083, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. E. S. K. Rijkers, T. P. Rygiel, T. de Ruiter, et al., “CD200 controls pathological T cell responses during influenza infection,” PLoS One, vol. 7, 2012.
  59. K. Yu, Z. Q. Chen, S. N. Wang, and R. Gorczynski, “Decreased alloreactivity using donor cells from mice expressing a CD200 transgene under control of a tetracycline-inducible promoter,” Transplantation, vol. 80, no. 3, pp. 394–401, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. R. M. Gorczynski, Z. Q. Chen, W. He et al., “Expression of a CD200 transgene is necessary for induction but not maintenance of tolerance to cardiac and skin allografts,” The Journal of Immunology, vol. 183, no. 3, pp. 1560–1568, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. R. M. Gorczynski, Z. Q. Chen, J. Diao et al., “Breast cancer cell CD200 expression regulates immune response to EMT6 tumor cells in mice,” Breast Cancer Research and Treatment, vol. 123, no. 2, pp. 405–415, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. K. Yu and R. Gorczynski, “Persistence of gene expression profile in CD200 transgenic skin allografts is associated with graft survival on retransplantation to normal recipients,” Transplantation, vol. 94, no. 1, pp. 36–42, 2012.
  63. I. Boudakov, J. Liu, N. Fan, P. Gulay, K. Wong, and R. M. Gorczynski, “Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-α and mixed leukocyte culture responses by CD200,” Transplantation, vol. 84, no. 2, pp. 251–257, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. R. M. Gorczynski, “CD200 and its receptors as targets for immunoregulation,” Current Opinion in Investigational Drugs, vol. 6, no. 5, pp. 483–488, 2005. View at Scopus
  65. R. M. Gorczynski, L. Lee, and I. Boudakov, “Augmented induction of CD4+CD25+ treg using monoclonal antibodies to CD200R,” Transplantation, vol. 79, no. 4, pp. 488–491, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. K. Yu, Z. Chen, and R. M. Gorczynski, “Effect of CD200 and CD200R1 expression within tissue grafts on increased graft survival in allogeneic recipients,” Immunology Letters. In press. View at Publisher · View at Google Scholar
  67. R. D. Stout and J. Suttles, “Functional plasticity of macrophages: reversible adaptation to changing microenvironments,” Journal of Leukocyte Biology, vol. 76, no. 3, pp. 509–513, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. R. D. Stout, S. K. Watkins, and J. Suttles, “Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages,” Journal of Leukocyte Biology, vol. 86, no. 5, pp. 1105–1109, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. Y. C. Ko, H. F. Chien, Y. F. Jiang-Shieh et al., “Endothelial CD200 is heterogeneously distributed, regulated and involved in immune cell-endothelium interactions,” Journal of Anatomy, vol. 214, no. 1, pp. 183–195, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. Z. Chen, P. A. Marsden, and R. M. Gorczynski, “Cloning and characterization of the human CD200 promoter region,” Molecular Immunology, vol. 43, no. 6, pp. 579–587, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. Z. Q. Chen, P. A. Marsden, and R. M. Gorczynski, “Role of a distal enhancer in the transcriptional responsiveness of the human CD200 gene to interferon-γ and tumor necrosis factor-α,” Molecular Immunology, vol. 46, no. 10, pp. 1951–1963, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. A. N. Barclay, “Membrane proteins with immunoglobulin-like domains—a master superfamily of interaction molecules,” Seminars in Immunology, vol. 15, no. 4, pp. 215–223, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Foster-Cuevas, G. J. Wright, M. J. Puklavec, M. H. Brown, and A. N. Barclay, “Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor,” Journal of Virology, vol. 78, no. 14, pp. 7667–7676, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Foster-Cuevas, T. Westerholt, M. Ahmed, M. H. Brown, A. N. Barclay, and S. Voigt, “Cytomegalovirus e127 protein interacts with the inhibitory CD200 receptor,” Journal of Virology, vol. 85, no. 12, pp. 6055–6059, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. C. M. Cameron, J. W. Barrett, L. Y. Liu, A. R. Lucas, and G. McFadden, “Myxoma virus M141R expresses a viral CD200 (vOX-2) that is responsible for down-regulation of macrophage and T-cell activation in vivo,” Journal of Virology, vol. 79, no. 10, pp. 6052–6067, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. H. Arase, E. S. Mocarski, A. E. Campbell, A. B. Hill, and L. L. Lanier, “Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors,” Science, vol. 296, no. 5571, pp. 1323–1326, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. S. J. Galli, J. Kalesnikoff, M. A. Grimbaldeston, A. M. Piliponsky, C. M. M. Williams, and M. Tsai, “Mast cells as “tunable” effector and immunoregulatory cells: recent advances,” Annual Review of Immunology, vol. 23, pp. 749–786, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. H. M. Cherwinski, C. A. Murphy, B. L. Joyce et al., “The CD200 receptor is a novel and potent regulator of murine and human mast cell function,” The Journal of Immunology, vol. 174, no. 3, pp. 1348–1356, 2005. View at Scopus
  79. R. M. Gorczynski, Z. Chen, H. Zeng, L. Gorczynski, and E. Terzioglu, “Analysis of cytokine production and Vβ T-cell receptor subsets in irradiated recipients receiving portal or peripheral venous reconstitution with allogeneic bone marrow cells, with or without additional anti-cytokine monoclonal antibodies,” Immunology, vol. 93, no. 2, pp. 221–229, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. R. M. Gorczynski, J. Hu, Z. Chen, Y. Kai, and J. Lei, “A CD200Fc immunoadhesin prolongs rat islet xenograft survival in mice,” Transplantation, vol. 73, no. 12, pp. 1948–1953, 2002. View at Scopus
  81. R. M. Gorczynski, K. Yu, and D. Clark, “Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo,” The Journal of Immunology, vol. 165, no. 9, pp. 4854–4860, 2000. View at Scopus
  82. R. M. Gorczynski, Z. Q. Chen, Y. Kai, S. Wong, and L. Lee, “Induction of tolerance-inducing antigen-presenting cells in bone marrow cultures in vitro using monoclonal antibodies to CD200R,” Transplantation, vol. 77, no. 8, pp. 1138–1144, 2004. View at Scopus
  83. K. Yu, Z. Chen, S. Wang, and R. M. Gorczynski, “Decreased alloreactivity using donor cells from mice expressing a CD200 transgene under control of a tetracycline-inducible promoter,” Transplantation, vol. 80, no. 3, pp. 394–401, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. R. M. Gorczynski, Z. Chen, I. Khatri, and K. Yu, “Graft-infiltrating cells expressing a CD200 transgene prolong allogeneic skin graft survival in association with local increases in Foxp3+Treg and mast cells,” Transplant Immunology, vol. 25, no. 4, pp. 187–193, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. K. Yu, Z. Chen, I. Khatri, and R. M. Gorczynski, “CCR4 dependent migration of Foxp3+ Treg cells to skin grafts and draining lymph nodes is implicated in enhanced graft survival in CD200tg recipients,” Immunology Letters, vol. 141, no. 1, pp. 116–122, 2011. View at Publisher · View at Google Scholar
  86. D. J. Chung, M. Rossi, E. Romano et al., “Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells,” Blood, vol. 114, no. 3, pp. 555–563, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. M. D. Sharma, D. Y. Hou, Y. Liu et al., “Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes,” Blood, vol. 113, no. 24, pp. 6102–6111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Onodera, M. H. Jang, Z. J. Guo et al., “Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions,” The Journal of Immunology, vol. 183, no. 9, pp. 5608–5614, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Piconese, G. Gri, C. Tripodo et al., “Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation,” Blood, vol. 114, no. 13, pp. 2639–2648, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley, and B. Stockinger, “TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells,” Immunity, vol. 24, no. 2, pp. 179–189, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Boerma, W. P. Fiser, G. Hoyt et al., “Influence of mast cells on outcome after heterotopic cardiac transplantation in rats,” Transplant International, vol. 20, no. 3, pp. 256–265, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. V. C. de Vries, A. Wasiuk, K. A. Bennett et al., “Mast cell degranulation breaks peripheral tolerance,” American Journal of Transplantation, vol. 9, no. 10, pp. 2270–2280, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Veldhoen, C. Uyttenhove, J. van Snick et al., “Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,” Nature Immunology, vol. 9, no. 12, pp. 1341–1346, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. W. Zhang, K. Wu, W. He et al., “Transforming growth factor beta 1 plays an important role in inducing CD4+CD25+forhead box P3+ regulatory T cells by mast cells,” Clinical and Experimental Immunology, vol. 161, no. 3, pp. 490–496, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. K. Eller, D. Wolf, J. M. Huber et al., “IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression,” The Journal of Immunology, vol. 186, no. 1, pp. 83–91, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. W. Elyaman, E. M. Bradshaw, C. Uyttenhove et al., “IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 12885–12890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. C. A. Da Silva, M. Adda, M. Stern, F. de Blay, N. Frossard, and D. Israel-Biet, “Marked stem cell factor expression in the airways of lung transplant recipients,” Respiratory Research, vol. 7, article 90, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Stassen, M. Arnold, L. Hültner et al., “Murine bone marrow-derived mast cells as potent producers of IL-9: costimulatory function of IL-10 and kit ligand in the presence of IL-1,” The Journal of Immunology, vol. 164, no. 11, pp. 5549–5555, 2000. View at Scopus
  99. R. Sembeil, K. Sanhadji, G. Vivier, J. Chargui, and J. L. Touraine, “Prolonged survival of mouse skin allografts after transplantation of fetal liver cells transduced with hIL-10 gene,” Transplant Immunology, vol. 13, no. 1, pp. 1–8, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. Z. Chen, D.-X. Chen, Y. Kai, I. Khatri, B. Lamptey, and R. M. Gorczynski, “Identification of an expressed truncated form of CD200, CD200tr, which is a physiologic antagonist of CD200-induced suppression,” Transplantation, vol. 86, no. 8, pp. 1116–1124, 2008. View at Publisher · View at Google Scholar · View at Scopus
  101. D. Miyazaki, T. Nakamura, M. Toda, K. W. Cheung-Chau, R. M. Richardson, and S. J. Ono, “Macrophage inflammatory protein-1α as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions,” The Journal of Clinical Investigation, vol. 115, no. 2, pp. 434–442, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. V. C. de Vries and R. J. Noelle, “Mast cell mediators in tolerance,” Current Opinion in Immunology, vol. 22, no. 5, pp. 643–648, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. C. P. Blobel, “ADAMs: key components in EGFR signalling and development,” Nature Reviews Molecular Cell Biology, vol. 6, no. 1, pp. 32–43, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. M. J. Duffy, E. McKiernan, N. O'Donovan, and P. M. McGowan, “The role of ADAMs in disease pathophysiology,” Clinica Chimica Acta, vol. 403, no. 1-2, pp. 31–36, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. X. Li, Z. R. Zhang, H. J. Schluesener, and S. Q. Xu, “Role of exosomes in immune regulation,” Journal of Cellular and Molecular Medicine, vol. 10, no. 2, pp. 364–375, 2006. View at Publisher · View at Google Scholar
  106. R. Simpson and S. Mathivanan, “Extracellular microvesicles: the need for internationally recognised nomenclature and stringent purification criteria,” Journal of Proteomics & Bioinformatics, vol. 2, pp. 1–9, 2012.
  107. P. P. Singh, V. L. Smith, P. C. Karakousis, and J. S. Schorey, “Exosomes isolated from mycobacteria-infected mice or cultured macrophages can recruit and activate immune cells in vitro and in vivo,” The Journal of Immunology, vol. 189, no. 2, pp. 777–785, 2012. View at Publisher · View at Google Scholar
  108. H. Peinado, M. Aleckovic, S. Lavotshkin, et al., “Melanoma exosomes educate bone marrow progenitor cells towar a pro-metastatic phenotype through MET,” Nature Medicine, vol. 18, pp. 883–891, 2012. View at Publisher · View at Google Scholar
  109. C. Yang, M. A. Ruffner, S.-H. Kim, and P. D. Robbins, “Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses,” European Journal of Immunology, vol. 42, no. 7, pp. 1778–1784, 2012. View at Publisher · View at Google Scholar
  110. R. M. Gorczynski, S. Hadidi, G. Yu, and D. A. Clark, “The same immunoregulatory molecules contribute to successful pregnancy and transplantation,” American Journal of Reproductive Immunology, vol. 48, no. 1, pp. 18–26, 2002. View at Publisher · View at Google Scholar · View at Scopus
  111. D. A. Clark and G. Chaouat, “Loss of surface CD200 on stored allogeneic leukocytes may impair anti-abortive effect in vivo,” American Journal of Reproductive Immunology, vol. 53, no. 1, pp. 13–20, 2005. View at Scopus
  112. D. A. Clark, K. Wong, D. Banwatt et al., “CD200-dependent and nonCD200-dependant pathways of NK cell suppression by human IVIG,” Journal of Assisted Reproduction and Genetics, vol. 25, no. 2-3, pp. 67–72, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. G. Yu, Y. Sun, K. Foerster et al., “LPS-induced murine abortions require C5 but not C3, and are prevented by upregulating expression of the CD200 tolerance signaling molecule,” American Journal of Reproductive Immunology, vol. 60, no. 2, pp. 135–140, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. D. A. Clark, J. Manuel, L. Lee, G. Chaouat, R. M. Gorczynski, and G. A. Levy, “Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA × DBA/2 mouse model. I. Synergistic effect of LPS (TNF-α + IFN-γ) on pregnancy loss,” American Journal of Reproductive Immunology, vol. 52, no. 6, pp. 370–378, 2004. View at Scopus
  115. D. X. Chen, H. He, and R. M. Gorczynski, “Synthetic peptides from the N-terminal regions of CD200 and CD200R1 modulate immunosuppressive and anti-inflammatory effects of CD200-CD200R1 interaction,” International Immunology, vol. 17, no. 3, pp. 289–296, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. D. X. Chen and R. M. Gorczynski, “Discrete monoclonal antibodies define functionally important epitopes in the CD200 molecule responsible for immunosuppression function,” Transplantation, vol. 79, no. 3, pp. 282–288, 2005. View at Publisher · View at Google Scholar · View at Scopus
  117. K. Kawamoto, A. Pahuja, B. J. Hering, and P. Bansal-Pakala, “Transforming growth factor beta 1 (TGF-β1) and rapamycin synergize to effectively suppress human T cell responses via upregulation of FoxP3+ Tregs,” Transplant Immunology, vol. 23, no. 1-2, pp. 28–33, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. R. M. Gorczynski, Z. Q. Chen, S. Shivagnahnam et al., “Potent immunosuppression by a bivalent molecule binding to CD200R and TGF-βR,” Transplantation, vol. 90, no. 2, pp. 150–159, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. R. M. Steinman, “Dendritic cells: understanding immunogenicity,” European Journal of Immunology, vol. 37, no. 1, pp. S53–S60, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. J. Mahoney and A. Rosen, “Apoptosis and autoimmunity,” Current Opinion in Immunology, vol. 17, no. 6, pp. 583–588, 2005. View at Publisher · View at Google Scholar
  121. F. Fallarino, U. Grohmann, S. You et al., “Tryptophan catabolism generates autoimmune-preventive regulatory T cells,” Transplant Immunology, vol. 17, no. 1, pp. 58–60, 2006. View at Publisher · View at Google Scholar · View at Scopus
  122. R. M. Gorczynski, Z. Q. Chen, K. Yu, and J. Hu, “CD200 immunoadhesin suppresses collagen-induced arthritis in mice,” Clinical Immunology, vol. 101, no. 3, pp. 328–334, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. R. M. Gorczynski, Z. Chen, L. Lee, K. Yu, and J. Hu, “Anti-CD200R ameliorates collagen-induced arthritis in mice,” Clinical Immunology, vol. 104, no. 3, pp. 256–264, 2002. View at Publisher · View at Google Scholar · View at Scopus
  124. M. C. Melnyk, I. Shalev, J. Zhang et al., “The prothrombinase activity of FGL2 contributes to the pathogenesis of experimental arthritis,” Scandinavian Journal of Rheumatology, vol. 40, no. 4, pp. 269–278, 2011. View at Publisher · View at Google Scholar
  125. E. Šimelyte, G. Criado, D. Essex, R. A. Uger, M. Feldmann, and R. O. Williams, “CD200-Fc, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis,” Arthritis and Rheumatism, vol. 58, no. 4, pp. 1038–1043, 2008. View at Publisher · View at Google Scholar · View at Scopus
  126. M. D. Rosenblum, K. B. Yancey, E. B. Olasz, and R. L. Truitt, “CD200, a “no danger” signal for hair follicles,” Journal of Dermatological Science, vol. 41, no. 3, pp. 165–174, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. N. Taylor, K. McConnachie, C. Calder et al., “Enhanced tolerance to autoimmune uveitis in CD200-deficient mice correlates with a pronounced Th2 switch in response to antigen challenge,” The Journal of Immunology, vol. 174, no. 1, pp. 143–154, 2005. View at Scopus
  128. A. D. Dick, Y. F. Cheng, J. Liversidge, and J. V. Forrester, “Immunomodulation of experimental autoimmune uveoretinitis: a model, of tolerance induction with retinal antigens,” Eye, vol. 8, part 1, pp. 52–59, 1994. View at Scopus
  129. D. A. Copland, C. J. Calder, B. J. E. Raveney et al., “Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis,” The American Journal of Pathology, vol. 171, no. 2, pp. 580–588, 2007. View at Publisher · View at Google Scholar · View at Scopus
  130. A. D. Dick, D. Carter, M. Robertson et al., “Control of myeloid activity during retinal inflammation,” Journal of Leukocyte Biology, vol. 74, no. 2, pp. 161–166, 2003. View at Publisher · View at Google Scholar · View at Scopus
  131. Y. Li, L. D. Zhao, L. S. Tong, et al., “Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity,” Arthritis Research & Therapy, vol. 14, article R123, 2012. View at Publisher · View at Google Scholar
  132. D. Banerjee and A. D. Dick, “Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats,” Ocular Immunology and Inflammation, vol. 12, no. 2, pp. 115–125, 2004. View at Publisher · View at Google Scholar · View at Scopus
  133. T. Chitnis, J. Imitola, Y. Wang et al., “Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration,” The American Journal of Pathology, vol. 170, no. 5, pp. 1695–1712, 2007. View at Publisher · View at Google Scholar · View at Scopus
  134. M. G. Frank, M. V. Baratta, D. B. Sprunger, L. R. Watkins, and S. F. Maier, “Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses,” Brain, Behavior, and Immunity, vol. 21, no. 1, pp. 47–59, 2007. View at Publisher · View at Google Scholar · View at Scopus
  135. H. Matsumoto, Y. Kumon, H. Watanabe et al., “Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion,” Neuroscience Letters, vol. 418, no. 1, pp. 44–48, 2007. View at Publisher · View at Google Scholar · View at Scopus
  136. D. G. Walker, J. E. Dalsing-Hernandez, N. A. Campbell, and L.-F. Lue, “Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation,” Experimental Neurology, vol. 215, no. 1, pp. 5–19, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. Z. Q. Chen, X. Z. Ma, J. H. Zhang, J. Hu, and R. M. Gorczynski, “Alternative splicing of CD200 is regulated by an exonic splicing enhancer and SF2/ASF,” Nucleic Acids Research, vol. 38, no. 19, pp. 6684–6696, 2010. View at Publisher · View at Google Scholar · View at Scopus
  138. S. Voight, G. R. Sandford, G. S. Hayward, and W. H. Burns, “The English strain of rat cytomegalovirus (CMV) contains a novel captured CD200 (vOX2) gene and a spliced CC chemokine upstream from the major immediate-early region: further evidence for a separate evolutionary lineage from that of a rat CMV Maastricht,” Journal of General Virology, vol. 86, no. 2, pp. 263–274, 2005. View at Publisher · View at Google Scholar · View at Scopus
  139. C. L. Pratt, R. D. Estep, and S. W. Wong, “Splicing of rhesus rhadinovirus R15 and ORF74 bicistronic transcripts during lytic infection and analysis of effects on production of vCD200 and vGPCR,” Journal of Virology, vol. 79, no. 6, pp. 3878–3882, 2005. View at Publisher · View at Google Scholar · View at Scopus
  140. S. Caserta, N. Nausch, A. Sawtell, et al., “Chronic infection drives expression of the inhibitory receptor CD200R, and its ligand CD200, by mouse and human CD4 T cells,” PLoS One, vol. 7, no. 4, Article ID e35466, 2012.
  141. R. M. Gorczynski, Z. Chen, J. Hu, Y. Kai, and J. Lei, “Evidence of a role for CD200 in regulation of immune rejection of leukaemic tumour cells in C57BL/6 mice,” Clinical and Experimental Immunology, vol. 126, no. 2, pp. 220–229, 2001. View at Publisher · View at Google Scholar · View at Scopus
  142. A. Tonks, R. Hills, P. White et al., “CD200 as a prognostic factor in acute myeloid leukaemia,” Leukemia, vol. 21, no. 3, pp. 566–568, 2007. View at Publisher · View at Google Scholar · View at Scopus
  143. J. R. McWhirter, A. Kretz-Rommel, A. Saven et al., “Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 4, pp. 1041–1046, 2006. View at Publisher · View at Google Scholar · View at Scopus
  144. J. Moreaux, D. Hose, T. Reme, et al., “CD200 is a new prognostic factor in multiple myeloma,” Blood, vol. 108, pp. 4194–4197, 2006. View at Scopus
  145. S. J. Coles, E. C. Y. Wang, S. Man et al., “CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia,” Leukemia, vol. 25, no. 5, pp. 792–799, 2011. View at Publisher · View at Google Scholar · View at Scopus
  146. J. Moreaux, J. L. Veyrune, T. Reme, J. de Vos, and B. Klein, “CD200: a putative therapeutic target in cancer,” Biochemical and Biophysical Research Communications, vol. 366, no. 1, pp. 117–122, 2008. View at Publisher · View at Google Scholar · View at Scopus
  147. R. R. Ruela-de-Sousa, K. C. Queiroz, M. P. Peppelenbosch, and G. M. Fuhler, “Reversible phosphorylation in haematological malignancies: potential role for protein tyrosine phosphatases in treatment?” Biochimica et Biophysica Acta, vol. 1806, no. 2, pp. 287–303, 2010. View at Scopus
  148. A. Kretz-Rommel, F. H. Qin, N. Dakappagari et al., “CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy,” The Journal of Immunology, vol. 178, no. 9, pp. 5595–5605, 2007. View at Scopus
  149. A. Kretz-Romme, F. Qin, N. Dakappagari, R. Cofiell, S. J. Faas, and K. S. Bowdish, “Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy,” The Journal of Immunology, vol. 180, no. 2, pp. 699–705, 2008. View at Scopus
  150. C. P. Pallasch, S. Ulbrich, R. Brinker, M. Hallek, R. A. Uger, and C.-M. Wendtner, “Disruption of T cell suppression in chronic lymphocytic leukemia by CD200 blockade,” Leukemia Research, vol. 33, no. 3, pp. 460–464, 2009. View at Publisher · View at Google Scholar · View at Scopus
  151. K. K. Wong, I. Khatri, S. Shaha, D. E. Spaner, and R. M. Gorczynski, “The role of CD200 in immunity to B cell lymphoma,” Journal of Leukocyte Biology, vol. 88, no. 2, pp. 361–372, 2010. View at Publisher · View at Google Scholar · View at Scopus
  152. K. K. Wong, F. Brenneman, A. Chesney, D. E. Spaner, and R. M. Gorczynski, “Soluble CD200 is critical to engraft chronic lymphocytic leukemia cells in immunocompromised mice,” Cancer Research, vol. 72, no. 19, pp. 4931–4943, 2012.
  153. A. Siva, H. Xin, F. Qin, D. Oltean, K. S. Bowdish, and A. Kretz-Rommel, “Immune modulation by melanoma and ovarian tumor cells through expression of the immunosuppressive molecule CD200,” Cancer Immunology, Immunotherapy, vol. 57, no. 7, pp. 987–996, 2008. View at Publisher · View at Google Scholar · View at Scopus
  154. M. Stumpfova, D. Ratner, E. B. Desciak, Y. D. Eliezri, and D. M. Owens, “The immunosuppressive surface ligand CD200 augments the metastatic capacity of squamous cell carcinoma,” Cancer Research, vol. 70, no. 7, pp. 2962–2972, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. Q. J. Huang, J. H. Yang, Y. Lin et al., “Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3,” Nature Immunology, vol. 5, no. 1, pp. 98–103, 2004. View at Publisher · View at Google Scholar · View at Scopus
  156. B. T. Kawasaki and W. L. Farrar, “Cancer stem cells, CD200 and immunoevasion,” Trends in Immunology, vol. 29, no. 10, pp. 464–468, 2008. View at Publisher · View at Google Scholar · View at Scopus
  157. K. B. Petermann, G. I. Rozenberg, D. Zedek et al., “CD200 is induced by ERK and is a potential therapeutic target in melanoma,” The Journal of Clinical Investigation, vol. 117, no. 12, pp. 3922–3929, 2007. View at Publisher · View at Google Scholar · View at Scopus
  158. K. Skalova, K. Mollova, and J. Michalek, “Human myeloid dendritic cells for cancer therapy: does maturation matter?” Vaccine, vol. 28, no. 32, pp. 5153–5160, 2010. View at Publisher · View at Google Scholar · View at Scopus
  159. A. Podnos, D. Clark, N. Erin, K. Yu, and R. M. Gorczynski, “Further evidence for a role of tumor CD200 expression in breast cancer metastasis: decreased metastasis in CD200R1KO mice or using CD200-silenced EMT6,” Breast Cancer Research and Treatment, vol. 136, no. 1, pp. 117–127, 2012. View at Publisher · View at Google Scholar
  160. F. Talebian, J.-Q. Liu, Z. Liu, M. Khattabi, and Y. He, “Melanoma cell expression of CD200 inhibits tumor formation and lung metastasis via inhibition of myeloid cell functions,” PLoS ONE, vol. 7, no. 2, Article ID e31442, 2012. View at Publisher · View at Google Scholar
  161. T. P. Rygiel and L. Meyaard, “CD200R signaling in tumor tolerance and inflammation: a tricky balance,” Current Opinion in Immunology, vol. 24, no. 2, pp. 233–238, 2012. View at Publisher · View at Google Scholar