IFN-γ decreased the suppressive function of CD33+HLA-DRlow myeloid cells through down-regulation of PD-1/PD-L2 signaling pathway

Mol Immunol. 2018 Feb:94:107-120. doi: 10.1016/j.molimm.2017.10.009. Epub 2018 Jan 4.

Abstract

Myeloid-derived suppressor cells (MDSCs) have recently been described to inhibit protective T-cell responses in tuberculosis (TB). T cells play an important role in the immunity to Mycobacterium tuberculosis, and are the major producers of IFN-γ. However, the impact of IFN-γ on MDSCs during TB is still not completely understood. Our study demonstrated a significant correlation between MDSC levels and TB progression, suggesting that MDSCs may serve as a potential marker in diagnosis or treatment of TB. Culture with GM-csf and IL-6 promoted peripheral blood mononuclear cells (PBMCs) to differentiate into functional CD33+HLA-DRlow MDSC-like cells. Moreover, we report for the first time, that IFN-γ-educated CD33+HLA-DRlow MDSCs have less suppressive potential to diminish T-cell responses, including IFN-γ production. Further investigations revealed that suppressive function of CD33+HLA-DRlow MDSCs was dependent on programmed death-1/programmed death-1 ligand-2 (PD1/PD-L2) pathway and required direct cell-cell contact. IFN-γ dampened the immuno-suppressive activity of CD33+HLA-DRlow MDSCs by inhibiting PD-1/PD-L2 pathway, indicating the existence of a negative-feedback loop between IFN-γ and functional MDSC expansion. In summary, our study revealed a novel mechanism by which IFN-γ decreases the suppressive function of MDSCs, suggesting that antagonizing suppressive functions of MDSCs by IFN-γ could enhance immune responses against TB infection.

Keywords: Interferon γ; Myeloid derived suppressor cells; Programmed death 1/programmed death 1 ligands; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Female
  • HLA-DR Antigens / metabolism*
  • Humans
  • Interferon-gamma / pharmacology*
  • Male
  • Middle Aged
  • Myeloid Cells / drug effects*
  • Myeloid Cells / pathology
  • Myeloid Cells / physiology
  • Programmed Cell Death 1 Ligand 2 Protein / metabolism*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Sialic Acid Binding Ig-like Lectin 3 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tuberculosis, Pulmonary / metabolism
  • Tuberculosis, Pulmonary / pathology
  • Young Adult

Substances

  • CD33 protein, human
  • HLA-DR Antigens
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Sialic Acid Binding Ig-like Lectin 3
  • Interferon-gamma