Properties of immature myeloid progenitors with nitric-oxide-dependent immunosuppressive activity isolated from bone marrow of tumor-free mice

PLoS One. 2013 Jul 2;8(7):e64837. doi: 10.1371/journal.pone.0064837. Print 2013.

Abstract

Myeloid derived suppressor cells (MDSCs) from tumor-bearing mice are important negative regulators of anti-cancer immune responses, but the role for immature myeloid cells (IMCs) in non-tumor-bearing mice in the regulation of immune responses are poorly described. We studied the immune-suppressive activity of IMCs from the bone marrow (BM) of C57Bl/6 mice and the mechanism(s) by which they inhibit T-cell activation and proliferation. IMCs, isolated from BM by high-speed FACS, inhibited mitogen-induced proliferation of CD4(+) and CD8(+) T-cells in vitro. Cell-to-cell contact of T-cells with viable IMCs was required for suppression. Neither neutralizing antibodies to TGFβ1, nor genetic disruption of indolamine 2,3-dioxygenase, abrogated IMC-mediated suppressive activity. In contrast, suppression of T-cell proliferation was absent in cultures containing IMCs from interferon-γ (IFN-γ) receptor KO mice or T-cells from IFN-γ KO mice (on the C57Bl/6 background). The addition of NO inhibitors to co-cultures of T-cells and IMC significantly reduced the suppressive activity of IMCs. IFN-γ signaling between T-cells and IMCs induced paracrine Nitric Oxide (NO) release in culture, and the degree of inhibition of T-cell proliferation was proportional to NO levels. The suppressive activity of IMCs from the bone marrow of tumor-free mice was comparable with MDSCs from BALB/c bearing mice 4T1 mammary tumors. These results indicate that IMCs have a role in regulating T-cell activation and proliferation in the BM microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Communication / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / deficiency
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Mammary Glands, Animal / immunology
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology*
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / cytology*
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / immunology
  • Nitric Oxide / metabolism*
  • Signal Transduction
  • Transforming Growth Factor beta1 / antagonists & inhibitors
  • Transforming Growth Factor beta1 / biosynthesis

Substances

  • Antibodies, Neutralizing
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Transforming Growth Factor beta1
  • Nitric Oxide
  • Interferon-gamma

Grants and funding

The authors have no support or funding to report.