ERMAP is a B7 family-related molecule that negatively regulates T cell and macrophage responses


T cell activation and tolerance are tightly regulated by costimulatory and coinhibitory molecules. B7 family members play a crucial role in regulating immune responses. In this study, we identified erythroid membrane-associated protein (ERMAP) as a novel T cell inhibitory molecule. ERMAP shares significant sequence and structural homology with existing B7 family members in its extracellular domain. The ERMAP protein is expressed on the cell surface of resting and activated antigen-presenting cells (APCs) and in some tumor tissues. The putative ERMAP receptor is expressed on activated CD4 and CD8 T cells and macrophages. Both mouse and human ERMAP-IgG2a Fc (ERMAP-Ig) fusion proteins inhibit T cell functions in vitro. Administration of ERMAP-Ig protein ameliorates autoimmune diseases, including experimental autoimmune encephalomyelitis and type 1 diabetes, in mice. Anti-ERMAP antibody enhances macrophage phagocytosis of cancer cells in vitro. Furthermore, administration of an anti-ERMAP antibody inhibits tumor growth in mice likely by blocking the inhibitory effects of ERMAP on T cells and macrophages. Our results suggest that therapeutic interaction with the ERMAP inhibitory pathway may represent a novel strategy for treating patients with autoimmune disease or cancer.

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  1. 1.

    Freeman, G. J. et al. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J. Exp. Med. 174, 625–631 (1991).

    CAS  PubMed  Google Scholar 

  2. 2.

    Freeman, G. J. et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 262, 909–911 (1993).

    CAS  PubMed  Google Scholar 

  3. 3.

    Dong, H., Zhu, G., Tamada, K. & Chen, L. B. 7-H. 1 a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365–1369 (1999).

    CAS  PubMed  Google Scholar 

  4. 4.

    Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).

    CAS  PubMed  Google Scholar 

  6. 6.

    Tseng, S. Y. et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193, 839–846 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Wang, S. et al. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood 96, 2808–13. (2000).

    CAS  PubMed  Google Scholar 

  8. 8.

    Ling, V. et al. Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. J. Immunol. 164, 1653–1657 (2000).

    CAS  PubMed  Google Scholar 

  9. 9.

    Swallow, M. M., Wallin, J. J. & Sha, W. C. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 11, 423–432 (1999).

    CAS  PubMed  Google Scholar 

  10. 10.

    Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999).

    CAS  PubMed  Google Scholar 

  11. 11.

    Chapoval, A. I. et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat. Immunol. 2, 269–274 (2001).

    CAS  PubMed  Google Scholar 

  12. 12.

    Prasad, D. V., Richards, S., Mai, X. M. & Dong, C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18, 863–873 (2003).

    CAS  PubMed  Google Scholar 

  13. 13.

    Sica, G. L. et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18, 849–861 (2003).

    CAS  PubMed  Google Scholar 

  14. 14.

    Zang, X. et al. B7x: a widely expressed B7 family member that inhibits T cell activation. Proc. Natl Acad. Sci. Usa. 100, 10388–10392 (2003).

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhao, R. et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc. Natl Acad. Sci. USA. 110, 9879–9884 (2013).

    CAS  PubMed  Google Scholar 

  16. 16.

    Zhu, Y. et al. B7-H5 costimulates human T cells via CD28H. Nat. Commun. 4, 2043 (2013).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Brandt, C. S. et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206, 1495–1503 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Abeler-Dorner, L., Swamy, M., Williams, G., Hayday, A. C. & Bas, A. Butyrophilins: an emerging family of immune regulators. Trends Immunol. 33, 34–41 (2012).

    PubMed  Google Scholar 

  19. 19.

    Afrache, H., Gouret, P., Ainouche, S., Pontarotti, P. & Olive, D. The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response. Immunogenetics 64, 781–794 (2012).

    CAS  PubMed  Google Scholar 

  20. 20.

    Arnett, H. A. & Viney, J. L. Immune modulation by butyrophilins. Nat. Rev. Immunol. 14, 559–569 (2014).

    CAS  PubMed  Google Scholar 

  21. 21.

    Guo, Y. & Wang, A. Y. Novel immune check-point regulators in tolerance maintenance. Front Immunol. 6, 421 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Rhodes, D. A., Reith, W. & Trowsdale, J. Regulation of immunity by butyrophilins. Annu Rev. Immunol. 34, 151–172 (2016).

    CAS  PubMed  Google Scholar 

  23. 23.

    Chapoval, A. I. et al. BTNL8, a butyrophilin-like molecule that costimulates the primary immune response. Mol. Immunol. 56, 819–828 (2013).

    CAS  PubMed  Google Scholar 

  24. 24.

    Nguyen, T., Liu, X. K., Zhang, Y. & Dong, C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. J. Immunol. 176, 7354–7360 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Arnett, H. A. et al. BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule modulated in intestinal inflammation. J. Immunol. 178, 1523–1533 (2007).

    CAS  PubMed  Google Scholar 

  26. 26.

    Yamazaki, T. et al. A butyrophilin family member critically inhibits T cell activation. J. Immunol. 185, 5907–5914 (2010).

    CAS  PubMed  Google Scholar 

  27. 27.

    Ammann, J. U., Cooke, A. & Trowsdale, J. Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes. J. Immunol. 190, 5030–5036 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Swanson, R. M. et al. Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells. J. Immunol. 190, 2027–2035 (2013).

    CAS  PubMed  Google Scholar 

  29. 29.

    Smith, I. A. et al. BTN1A1, the mammary gland butyrophilin, and BTN2A2 are both inhibitors of T cell activation. J. Immunol. (Baltim., Md: 1950). 184, 3514–3525 (2010).

    CAS  Google Scholar 

  30. 30.

    Cubillos-Ruiz, J. R. et al. CD277 is a negative co-stimulatory molecule universally expressed by ovarian cancer microenvironmental cells. Oncotarget 1, 329–338 (2010).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Compte, E., Pontarotti, P., Collette, Y., Lopez, M. & Olive, D. Frontline: characterization of BT3 molecules belonging to the B7 family expressed on immune cells. Eur. J. Immunol. 34, 2089–2099 (2004).

    CAS  PubMed  Google Scholar 

  32. 32.

    Yamashiro, H., Yoshizaki, S., Tadaki, T., Egawa, K. & Seo, N. Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J. Leukoc. Biol. 88, 757–767 (2010).

    CAS  PubMed  Google Scholar 

  33. 33.

    Palakodeti, A. et al. The molecular basis for modulation of human Vgamma9Vdelta2 T cell responses by CD277/butyrophilin-3 (BTN3A)-specific antibodies. J. Biol. Chem. 287, 32780–32790 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Linsley, P. S., Peach, R., Gladstone, P. & Bajorath, J. Extending the B7 (CD80) gene family. Protein Sci. 3, 1341–1343 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Yang, Y. et al. Characterization of B7S3 as a novel negative regulator of T cells. J. Immunol. 178, 3661–3667 (2007).

    CAS  PubMed  Google Scholar 

  36. 36.

    Arnett, H. A., Escobar, S. S. & Viney, J. L. Regulation of costimulation in the era of butyrophilins. Cytokine 46, 370–375 (2009).

    CAS  PubMed  Google Scholar 

  37. 37.

    Su, Y. Y., Gordon, C. T., Ye, T. Z., Perkins, A. C. & Chui, D. H. Human ERMAP: an erythroid adhesion/receptor transmembrane protein. Blood Cell Mol. Dis. 27, 938–949 (2001).

    CAS  Google Scholar 

  38. 38.

    Xu, H. et al. Cloning and characterization of human erythroid membrane-associated protein, human ERMAP. Genomics 76, 2–4 (2001).

    CAS  PubMed  Google Scholar 

  39. 39.

    Jin, J., Goldschneider, I. & Lai, L. In vivo administration of the recombinant IL-7/hepatocyte growth factor beta hybrid cytokine efficiently restores thymopoiesis and naive T cell generation in lethally irradiated mice after syngeneic bone marrow transplantation. J. Immunol. 186, 1915–1922 (2011).

    CAS  PubMed  Google Scholar 

  40. 40.

    Lai, L., Zhang, M. & Goldschneider, I. Recombinant IL-7/HGFbeta efficiently induces transplantable murine hematopoietic stem cells. J. Clin. Investig. 122, 3552–3562 (2012).

    CAS  PubMed  Google Scholar 

  41. 41.

    Lai, L., Zhang, M., Song, Y. & Rood, D. Recombinant IL-7/HGFbeta hybrid cytokine enhances T cell recovery in mice following allogeneic bone marrow transplantation. PloS One 8, e82998 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Song, Y., Su, M., Panchatsharam, P., Rood, D. & Lai, L. c-Met signalling is required for efficient postnatal thymic regeneration and repair. Immunology 144, 245–253 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Su, M. et al. Administration of embryonic stem cell-derived thymic epithelial progenitors expressing MOG induces antigen-specific tolerance and ameliorates experimental autoimmune encephalomyelitis. J. Autoimmun. 58, 36–47 (2015).

    CAS  PubMed  Google Scholar 

  44. 44.

    Yan, Y. et al. Tbx1 modulates endodermal and mesodermal differentiation from mouse induced pluripotent stem cells. Stem Cells Dev. 23, 1491–1500 (2014).

  45. 45.

    Lin, Y. et al. Skint8, a novel B7 family-related molecule, negatively regulates T cell responses. J. Immunol. 203, 400–407 (2019).

  46. 46.

    Pineda-Torra, I., Gage, M., de Juan, A. & Pello, O. M. Isolation, culture, and polarization of murine bone marrow-derived and peritoneal macrophages. Methods Mol. Biol. 1339, 101–109 (2015).

    CAS  PubMed  Google Scholar 

  47. 47.

    Hofmeyer, K. A., Ray, A. & Zang, X. The contrasting role of B7-H3. Proc. Natl Acad. Sci. USA 105, 10277–10278 (2008).

    CAS  PubMed  Google Scholar 

  48. 48.

    Prasad, D. V. R. et al. Murine B7-H3 is a negative regulator of T cells. J. Immunol. 173, 2500–2506 (2004).

    CAS  PubMed  Google Scholar 

  49. 49.

    Ye, T. Z. et al. Ermap, a gene coding for a novel erythroid specific adhesion/receptor membrane protein. Gene 242, 337–345 (2000).

    CAS  PubMed  Google Scholar 

  50. 50.

    Patsoukis, N. et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal. 5, ra46 (2012).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    CAS  PubMed  Google Scholar 

  52. 52.

    Weiskopf, K. & Weissman, I. L. Macrophages are critical effectors of antibody therapies for cancer. mAbs 7, 303–310 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    CAS  PubMed  Google Scholar 

  54. 54.

    Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu Rev. Immunol. 23, 447–485 (2005).

    CAS  PubMed  Google Scholar 

  55. 55.

    Zhang, X., Schwartz, J. C., Almo, S. C. & Nathenson, S. G. Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling. Proc. Natl Acad. Sci. USA 100, 2586–2591 (2003).

    CAS  PubMed  Google Scholar 

  56. 56.

    Brown, E. J. & Frazier, W. A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).

    CAS  PubMed  Google Scholar 

  57. 57.

    Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Mana, P. et al. Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin. Int Immunol. 16, 489–499 (2004).

    CAS  PubMed  Google Scholar 

  59. 59.

    Stefferl, A. et al. Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J. Immunol. 165, 2859–2865 (2000).

    CAS  PubMed  Google Scholar 

  60. 60.

    Podojil, J. R. et al. B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms. J. Autoimmun. 44, 71–81 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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We would like to thank Qingquan Chen for technical assistance. This work was supported by grants from the NIH (1R01AI123131–01) and the Connecticut Regenerative Medicine Research Fund (16-RMB-UCONN-02).

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Author contributions: L.L. designed the research studies. M.S., Y. L, C.C., X.T., and L.L. conducted the experiments, acquired data, and analyzed data. L.L. wrote the paper and provided funding.

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Correspondence to Laijun Lai.

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Su, M., Lin, Y., Cui, C. et al. ERMAP is a B7 family-related molecule that negatively regulates T cell and macrophage responses. Cell Mol Immunol (2020).

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  • T cells
  • T cell inhibitory molecules
  • autoimmunity
  • EAE


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