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

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.