Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Bone marrow and the control of immunity

Cellular & Molecular Immunology volume 9, pages 11–19 (2012)Cite this article

Abstract

Bone marrow is thought to be a primary hematopoietic organ. However, accumulated evidences demonstrate that active function and trafficking of immune cells, including regulatory T cells, conventional T cells, B cells, dendritic cells, natural killer T (NKT) cells, neutrophils, myeloid-derived suppressor cells and mesenchymal stem cells, are observed in the bone marrow. Furthermore, bone marrow is a predetermined metastatic location for multiple human tumors. In this review, we discuss the immune network in the bone marrow. We suggest that bone marrow is an immune regulatory organ capable of fine tuning immunity and may be a potential therapeutic target for immunotherapy and immune vaccination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Kopp HG, Avecilla ST, Hooper AT, Rafii S . The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 2005; 20: 349–356.

    CAS  Google Scholar 

  2. Rafii S, Lyden D . Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003; 9: 702–712.

    Article  CAS  PubMed  Google Scholar 

  3. Tripp RA, Topham DJ, Watson SR, Doherty PC . Bone marrow can function as a lymphoid organ during a primary immune response under conditions of disrupted lymphocyte trafficking. J Immunol 1997; 158: 3716–3720.

    CAS  PubMed  Google Scholar 

  4. Dejbakhsh-Jones S, Jerabek L, Weissman IL, Strober S . Extrathymic maturation of alpha beta T cells from hemopoietic stem cells. J Immunol 1995; 155: 3338–3344.

    CAS  PubMed  Google Scholar 

  5. Schirrmacher V, Feuerer M, Fournier P, Ahlert T, Umansky V, Beckhove P . T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends Mol Med 2003; 9: 526–534.

    Article  CAS  PubMed  Google Scholar 

  6. Feuerer M, Beckhove P, Mahnke Y, Hommel M, Kyewski B, Hamann A et al. Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory. Int J Oncol 2004; 25: 867–876.

    PubMed  Google Scholar 

  7. Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M et al. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med 2003; 9: 1151–1157.

    Article  CAS  PubMed  Google Scholar 

  8. Mazo IB, Honczarenko M, Leung H, Cavanagh LL, Bonasio R, Weninger W et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 2005; 22: 259–270.

    Article  CAS  PubMed  Google Scholar 

  9. Slifka MK, Whitmire JK, Ahmed R . Bone marrow contains virus-specific cytotoxic T lymphocytes. Blood 1997; 90: 2103–2108.

    Article  CAS  PubMed  Google Scholar 

  10. Zeng D, Hoffmann P, Lan F, Huie P, Higgins J, Strober S . Unique patterns of surface receptors, cytokine secretion, and immune functions distinguish T cells in the bone marrow from those in the periphery: impact on allogeneic bone marrow transplantation. Blood 2002; 99: 1449–1457.

    Article  CAS  PubMed  Google Scholar 

  11. Price PW, Cerny J . Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vbeta repertoire. Eur J Immunol 1999; 29: 1051–1056.

    Article  CAS  PubMed  Google Scholar 

  12. Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res 2004; 64: 8451–8455.

    Article  CAS  PubMed  Google Scholar 

  13. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767–811.

    Article  CAS  PubMed  Google Scholar 

  14. Sykes M . Unusual T cell populations in adult murine bone marrow. Prevalence of CD3+CD4−CD8− and alpha beta TCR+NK1.1+ cells. J Immunol 1990; 145: 3209–3215.

    CAS  PubMed  Google Scholar 

  15. Higuchi M, Zeng D, Shizuru J, Gworek J, Dejbakhsh-Jones S, Taniguchi M et al. Immune tolerance to combined organ and bone marrow transplants after fractionated lymphoid irradiation involves regulatory NK T cells and clonal deletion. J Immunol 2002; 169: 5564–5570.

    Article  CAS  PubMed  Google Scholar 

  16. Zeng D, Gazit G, Dejbakhsh-Jones S, Balk SP, Snapper S, Taniguchi M et al. Heterogeneity of NK1.1+ T cells in the bone marrow: divergence from the thymus. J Immunol 1999; 163: 5338–5345.

    CAS  PubMed  Google Scholar 

  17. Fry TJ, Mackall CL . The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 2005; 174: 6571–6576.

    Article  CAS  PubMed  Google Scholar 

  18. Geginat J, Sallusto F, Lanzavecchia A . Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J Exp Med 2001; 194: 1711–1719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD . Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med 2002; 195: 1523–1532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lantz O, Grandjean I, Matzinger P, Di Santo JP . Gamma chain required for naive CD4+ T cell survival but not for antigen proliferation. Nat Immunol 2000; 1: 54–58.

    Article  CAS  PubMed  Google Scholar 

  21. Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M et al. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 2007; 67: 7487–7494.

    Article  CAS  PubMed  Google Scholar 

  22. Wei S, Kryczek I, Zou W . Regulatory T-cell compartmentalization and trafficking. Blood 2006; 108: 426–431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 2004; 10: 64–71.

    Article  CAS  PubMed  Google Scholar 

  24. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–48.

    Article  PubMed  Google Scholar 

  25. Herrmann MM, Gaertner S, Stadelmann C, van den Brandt J, Boscke R, Budach W et al. Tolerance induction by bone marrow transplantation in a multiple sclerosis model. Blood 2005; 106: 1875–1883.

    Article  CAS  PubMed  Google Scholar 

  26. Kryczek I, Liu R, Wang G, Wu K, Shu X, Szeliga W et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res 2009; 69: 3995–4000.

    Article  CAS  PubMed  Google Scholar 

  27. Wilke CM, Wu K, Zhao E, Wang G, Zou W . Prognostic significance of regulatory T cells in tumor. Int J Cancer 2010; 127: 748–758.

    CAS  PubMed  Google Scholar 

  28. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942–949.

    Article  CAS  PubMed  Google Scholar 

  29. Issa F, Wood KJ . CD4+ regulatory T cells in solid organ transplantation. Curr Opin Organ Transplant 2010; 15: 757–764.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.

    Article  CAS  PubMed  Google Scholar 

  31. Zou W . Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6: 295–307.

    Article  CAS  PubMed  Google Scholar 

  32. Zou W, Restifo NP . T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 2011; 10: 248–256.

    Article  CAS  Google Scholar 

  33. Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W et al. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood 2010; 115: 5385–5392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009; 114: 1141–1149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kryczek I, Wei S, Vatan L, Escara-Wilke J, Szeliga W, Keller ET et al. Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J Immunol 2007; 179: 1423–1426.

    Article  CAS  PubMed  Google Scholar 

  36. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271–2279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W . Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 2009; 114: 357–359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 2008; 181: 4733–4741.

    Article  CAS  PubMed  Google Scholar 

  39. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 2007; 178: 6730–6733.

    Article  CAS  PubMed  Google Scholar 

  40. Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I . A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood 2010; 116: 3554–3563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ghannam S, Pene J, Torcy-Moquet G, Jorgensen C, Yssel H . Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 2010; 185: 302–312.

    Article  CAS  PubMed  Google Scholar 

  42. Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009; 57: 1192–1203.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kong QF, Sun B, Wang GY, Zhai DX, Mu LL, Wang DD et al. BM stromal cells ameliorate experimental autoimmune myasthenia gravis by altering the balance of Th cells through the secretion of IDO. Eur J Immunol 2009; 39: 800–809.

    Article  CAS  PubMed  Google Scholar 

  44. Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 2009; 113: 945–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR . Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood 2007; 110: 3804–3813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kordasti SY, Afzali B, Lim Z, Ingram W, Hayden J, Barber L et al. IL-17-producing CD4+ T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. Br J Haematol 2009; 145: 64–72.

    Article  CAS  PubMed  Google Scholar 

  47. Becker TC, Coley SM, Wherry EJ, Ahmed R . Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J Immunol 2005; 174: 1269–1273.

    Article  CAS  PubMed  Google Scholar 

  48. Marshall DR, Turner SJ, Belz GT, Wingo S, Andreansky S, Sangster MY et al. Measuring the diaspora for virus-specific CD8+ T cells. Proc Natl Acad Sci USA 2001; 98: 6313–6318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Masopust D, Vezys V, Marzo AL, Lefrancois L . Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291: 2413–2417.

    Article  CAS  PubMed  Google Scholar 

  50. Parretta E, Cassese G, Barba P, Santoni A, Guardiola J, Di Rosa F . CD8 cell division maintaining cytotoxic memory occurs predominantly in the bone marrow. J Immunol 2005; 174: 7654–7664.

    Article  CAS  PubMed  Google Scholar 

  51. Weninger W, Crowley MA, Manjunath N, von Andrian UH . Migratory properties of naive, effector, and memory CD8+ T cells. J Exp Med 2001; 194: 953–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kronenberg M . Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol 2005; 23: 877–900.

    Article  CAS  PubMed  Google Scholar 

  53. MacDonald HR . NK1.1+ T cell receptor-alpha/beta+ cells: new clues to their origin, specificity, and function. J Exp Med 1995; 182: 633–638.

    Article  CAS  PubMed  Google Scholar 

  54. Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci USA 2001; 98: 8732–8737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kikly K, Dennert G . Evidence for extrathymic development of TNK cells. NK1+ CD3+ cells responsible for acute marrow graft rejection are present in thymus-deficient mice. J Immunol 1992; 149: 403–412.

    CAS  PubMed  Google Scholar 

  56. Sato K, Ohtsuka K, Hasegawa K, Yamagiwa S, Watanabe H, Asakura H et al. Evidence for extrathymic generation of intermediate T cell receptor cells in the liver revealed in thymectomized, irradiated mice subjected to bone marrow transplantation. J Exp Med 1995; 182: 759–767.

    Article  CAS  PubMed  Google Scholar 

  57. Haraguchi K, Takahashi T, Hiruma K, Kanda Y, Tanaka Y, Ogawa S et al. Recovery of Valpha24+ NKT cells after hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 34: 595–602.

    Article  CAS  PubMed  Google Scholar 

  58. Margalit M, Ilan Y, Ohana M, Safadi R, Alper R, Sherman Y et al. Adoptive transfer of small numbers of DX5+ cells alleviates graft-versus-host disease in a murine model of semiallogeneic bone marrow transplantation: a potential role for NKT lymphocytes. Bone Marrow Transplant 2005; 35: 191–197.

    Article  CAS  PubMed  Google Scholar 

  59. Smyth MJ, Crowe NY, Hayakawa Y, Takeda K, Yagita H, Godfrey DI . NKT cells - conductors of tumor immunity? Curr Opin Immunol 2002; 14: 165–171.

    Article  CAS  PubMed  Google Scholar 

  60. Dean J, McCarthy D, Lawler M, Doherty DG, O'Farrelly C, Golden-Mason L . Characterization of NKR+ T-cell subsets in human bone marrow: implications for immunosurveillance of neoplasia. Clin Immunol 2005; 114: 42–51.

    Article  CAS  PubMed  Google Scholar 

  61. Zeng D, Lewis D, Dejbakhsh-Jones S, Lan F, Garcia-Ojeda M, Sibley R et al. Bone marrow NK1.1− and NK1.1+ T cells reciprocally regulate acute graft versus host disease. J Exp Med 1999; 189: 1073–1081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T . Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 2004; 20: 707–718.

    Article  CAS  PubMed  Google Scholar 

  63. Sandel PC, Gendelman M, Kelsoe G, Monroe JG . Definition of a novel cellular constituent of the bone marrow that regulates the response of immature B cells to B cell antigen receptor engagement. J Immunol 2001; 166: 5935–5944.

    Article  CAS  PubMed  Google Scholar 

  64. Slifka MK, Antia R, Whitmire JK, Ahmed R . Humoral immunity due to long-lived plasma cells. Immunity 1998; 8: 363–372.

    Article  CAS  PubMed  Google Scholar 

  65. Manz RA, Thiel A, Radbruch A . Lifetime of plasma cells in the bone marrow. Nature 1997; 388: 133–134.

    Article  CAS  PubMed  Google Scholar 

  66. Minges Wols HA, Underhill GH, Kansas GS, Witte PL . The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J Immunol 2002; 169: 4213–4221.

    Article  CAS  PubMed  Google Scholar 

  67. Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, Suzuki G et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J Exp Med 2001; 194: 45–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hauser AE, Debes GF, Arce S, Cassese G, Hamann A, Radbruch A et al. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 2002; 169: 1277–1282.

    Article  CAS  PubMed  Google Scholar 

  69. Tokoyoda K, Hauser AE, Nakayama T, Radbruch A . Organization of immunological memory by bone marrow stroma. Nat Rev Immunol 2010; 10: 193–200.

    Article  CAS  PubMed  Google Scholar 

  70. Nathan C . Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006; 6: 173–182.

    Article  CAS  PubMed  Google Scholar 

  71. Christopher MJ, Link DC . Regulation of neutrophil homeostasis. Curr Opin Hematol 2007; 14: 3–8.

    Article  CAS  PubMed  Google Scholar 

  72. Borregaard N . Neutrophils, from marrow to microbes. Immunity 2010; 33: 657–670.

    Article  CAS  PubMed  Google Scholar 

  73. Rosmarin AG, Yang Z, Resendes KK . Transcriptional regulation in myelopoiesis: hematopoietic fate choice, myeloid differentiation, and leukemogenesis. Exp Hematol 2005; 33: 131–143.

    Article  CAS  PubMed  Google Scholar 

  74. Ray D, Culine S, Tavitain A, Moreau-Gachelin F . The human homologue of the putative proto-oncogene Spi-1: characterization and expression in tumors. Oncogene 1990; 5: 663–668.

    CAS  PubMed  Google Scholar 

  75. Nerlov C, Graf T . PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors. Genes Dev 1998; 12: 2403–2412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 2005; 106: 1590–1600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK et al. Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood 2002; 100: 483–490.

    Article  CAS  PubMed  Google Scholar 

  78. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol 2003; 4: 1029–1036.

    Article  CAS  PubMed  Google Scholar 

  79. Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 2006; 126: 755–766.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 1997; 94: 569–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Karsunky H, Zeng H, Schmidt T, Zevnik B, Kluge R, Schmid KW et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat Genet 2002; 30: 295–300.

    Article  PubMed  Google Scholar 

  82. Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S et al. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 2003; 18: 109–120.

    Article  CAS  PubMed  Google Scholar 

  83. Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L et al. The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci USA 1989; 86: 9499–9503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Richards MK, Liu F, Iwasaki H, Akashi K, Link DC . Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 2003; 102: 3562–3568.

    Article  CAS  PubMed  Google Scholar 

  85. Cartwright GE, Athens JW, Wintrobe MM . The kinetics of granulopoiesis in normal man. Blood 1964; 24: 780–803.

    Article  CAS  PubMed  Google Scholar 

  86. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC . G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 2002; 17: 413–423.

    Article  CAS  PubMed  Google Scholar 

  87. Eash KJ, Means JM, White DW, Link DC . CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 2009; 113: 4711–4719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM . Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003; 19: 583–593.

    Article  CAS  PubMed  Google Scholar 

  89. Semerad CL, Christopher MJ, Liu F, Short B, Simmons PJ, Winkler I et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005; 106: 3020–3027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Christopher MJ, Liu F, Hilton MJ, Long F, Link DC . Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood 2009; 114: 1331–1339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rankin SM . The bone marrow: a site of neutrophil clearance. J Leukoc Biol 2010; 88: 241–251.

    Article  CAS  PubMed  Google Scholar 

  92. Furze RC, Rankin SM . The role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse. FASEB J 2008; 22: 3111–3119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nagase H, Miyamasu M, Yamaguchi M, Imanishi M, Tsuno NH, Matsushima K et al. Cytokine-mediated regulation of CXCR4 expression in human neutrophils. J Leukoc Biol 2002; 71: 711–717.

    CAS  PubMed  Google Scholar 

  94. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S . Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 2002; 20: 621–667.

    Article  CAS  PubMed  Google Scholar 

  95. Cavanagh LL, Bonasio R, Mazo IB, Halin C, Cheng G, van der Velden AW et al. Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat Immunol 2005; 6: 1029–1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sallusto F, Geginat J, Lanzavecchia A . Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 2004; 22: 745–763.

    Article  CAS  PubMed  Google Scholar 

  97. Gabrilovich DI, Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gabrilovich D . Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 2004; 4: 941–952.

    Article  CAS  PubMed  Google Scholar 

  99. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI . Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004; 172: 989–999.

    Article  CAS  PubMed  Google Scholar 

  100. Kusmartsev S, Gabrilovich DI . Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 2006; 55: 237–245.

    Article  PubMed  Google Scholar 

  101. Movahedi K, Guilliams M, van den Bossche J, van den Bergh R, Gysemans C, Beschin A et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 2008; 111: 4233–4244.

    Article  CAS  PubMed  Google Scholar 

  102. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI . Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008; 181: 5791–5802.

    Article  CAS  PubMed  Google Scholar 

  103. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC . Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 2007; 13: 721s 726s.

    Article  CAS  PubMed  Google Scholar 

  104. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001; 166: 678–689.

    Article  CAS  PubMed  Google Scholar 

  105. Yang R, Cai Z, Zhang Y, Yutzy WH 4 th, Roby KF, Roden RB . CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res 2006; 66: 6807–6815.

    Article  CAS  PubMed  Google Scholar 

  106. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 2006; 66: 1123–1131.

    Article  CAS  PubMed  Google Scholar 

  107. Ribechini E, Greifenberg V, Sandwick S, Lutz MB . Subsets, expansion and activation of myeloid-derived suppressor cells. Med Microbiol Immunol 2010; 199: 273–281.

    Article  CAS  PubMed  Google Scholar 

  108. Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R et al. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 2010; 116: 5738–5747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Caplan AI . Mesenchymal stem cells. J Orthop Res 1991; 9: 641–650.

    Article  CAS  PubMed  Google Scholar 

  110. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O . HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31: 890–896.

    Article  CAS  PubMed  Google Scholar 

  111. Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 2005; 12: 47–57.

    Article  CAS  PubMed  Google Scholar 

  112. Majumdar MK, Thiede MA, Haynesworth SE, Bruder SP, Gerson SL . Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother Stem Cell Res 2000; 9: 841–848.

    Article  CAS  PubMed  Google Scholar 

  113. Cheng L, Hammond H, Ye Z, Zhan X, Dravid G . Human adult marrow cells support prolonged expansion of human embryonic stem cells in culture. Stem Cells 2003; 21: 131–142.

    Article  CAS  PubMed  Google Scholar 

  114. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O . Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57: 11–20.

    Article  CAS  PubMed  Google Scholar 

  115. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  PubMed  Google Scholar 

  116. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101: 3722–3729.

    Article  CAS  PubMed  Google Scholar 

  117. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F . Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–2827.

    Article  CAS  PubMed  Google Scholar 

  118. Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC . Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 2005; 19: 1597–1604.

    Article  CAS  PubMed  Google Scholar 

  119. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.

    Article  CAS  PubMed  Google Scholar 

  120. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P . Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 2003; 171: 3426–3434.

    Article  CAS  PubMed  Google Scholar 

  121. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107: 367–372.

    Article  CAS  PubMed  Google Scholar 

  122. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105: 4120–4126.

    Article  CAS  PubMed  Google Scholar 

  123. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE . Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 2006; 177: 2080–2087.

    Article  CAS  PubMed  Google Scholar 

  124. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M . Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24: 74–85.

    Article  PubMed  Google Scholar 

  125. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L . Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008; 111: 1327–1333.

    Article  CAS  PubMed  Google Scholar 

  126. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI . Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 1995; 16: 557–564.

    CAS  PubMed  Google Scholar 

  127. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5: 309–313.

    Article  CAS  PubMed  Google Scholar 

  128. Bang OY, Lee JS, Lee PH, Lee G . Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005; 57: 874–882.

    Article  PubMed  Google Scholar 

  129. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004; 94: 92–95.

    Article  PubMed  Google Scholar 

  130. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.

    Article  CAS  PubMed  Google Scholar 

  131. Miller JP, Izon D, DeMuth W, Gerstein R, Bhandoola A, Allman D . The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J Exp Med 2002; 196: 705–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 1994; 180: 1955–1960.

    Article  CAS  PubMed  Google Scholar 

  133. Roifman CM, Zhang J, Chitayat D, Sharfe N . A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood 2000; 96: 2803–2807.

    Article  CAS  PubMed  Google Scholar 

  134. Schluns KS, Kieper WC, Jameson SC, Lefrancois L . Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 2000; 1: 426–432.

    Article  CAS  PubMed  Google Scholar 

  135. Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R, Ma A et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 2002; 195: 1541–1548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kieper WC, Tan JT, Bondi-Boyd B, Gapin L, Sprent J, Ceredig R et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J Exp Med 2002; 195: 1533–1539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 2004; 101: 1969–1974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Di Carlo E, Comes A, Orengo AM, Rosso O, Meazza R, Musiani P et al. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. J Immunol 2004; 172: 1540–1547.

    Article  CAS  PubMed  Google Scholar 

  139. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000; 408: 57–63.

    Article  CAS  PubMed  Google Scholar 

  140. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.

    Article  CAS  PubMed  Google Scholar 

  141. Peled A, Grabovsky V, Habler L, Sandbank J, Arenzana-Seisdedos F, Petit I et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest 1999; 104: 1199–1211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S, Grabovsky V et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood 2000; 95: 3289–3296.

    Article  CAS  PubMed  Google Scholar 

  143. Lapidot T, Kollet O . The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 2002; 16: 1992–2003.

    Article  CAS  PubMed  Google Scholar 

  144. Ma Q, Jones D, Springer TA . The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10: 463–471.

    Article  CAS  PubMed  Google Scholar 

  145. Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 2004; 103: 2981–2989.

    Article  CAS  PubMed  Google Scholar 

  146. Koni PA, Joshi SK, Temann UA, Olson D, Burkly L, Flavell RA . Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med 2001; 193: 741–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Frenette PS, Subbarao S, Mazo IB, von Andrian UH, Wagner DD . Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc Natl Acad Sci USA 1998; 95: 14423–14428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research is supported (in part) by NIH/NCI R01 grants (R01CA133620) (WZ) and the NIH through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592).

Author information

Author notes

  1. Ende Zhao and Huanbin Xu: These two authors contributed equally to this work.

  2. Dr Weiping Zou, University of Michigan School of Medicine, C560B MSRB II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0669, USA. E-mail: wzou@med.umich.edu

Authors and Affiliations

  1. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Ende Zhao, Ilona Kryczek & Weiping Zou

  2. Union Hospital, Huazhong University of Science and Technology School of Medicine, Wuhan, China

    Ende Zhao, Lin Wang, Ke Wu, Yu Hu & Guobin Wang

  3. Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA

    Huanbin Xu

  4. Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Weiping Zou

  5. Graduate Program in Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Weiping Zou

  6. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Weiping Zou

Authors
  1. Ende Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huanbin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilona Kryczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ke Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guobin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weiping Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, E., Xu, H., Wang, L. et al. Bone marrow and the control of immunity. Cell Mol Immunol 9, 11–19 (2012). https://doi.org/10.1038/cmi.2011.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2011.47

Keywords

This article is cited by

Search

Advanced search

Quick links