IFN-γ differentially regulates subsets of Gr-1+CD11b+ myeloid cells in chronic inflammation

•Heat-killed BCG induced-chronic inflammation drove two subpopulations of CD11b+Gr-1+ myeloid cells in the mouse spleen.•IFN-γ dampened nuetrophil-like myeloid derived inducer cells-mediated T cell activation and proliferation through up-regulating arginase activity and ROS production.•IFN-γ reduced monocyte-like myeloid derived suppressor cells-mediated suppressing activity by decreasing the their arginase activity.

During chronic inflammation, prolonged over-reactive immune response may lead to tissue destruction, while immune suppression hinders tissue repair and pathogen elimination. Therefore, precise regulation of the immune response is needed to avoid immuno-pathology. Interferon-gamma (IFN-γ) is widely used in clinical treatment of inflammatory diseases. However, the underlying mechanism remains unclear. Here, we evaluated the role of IFN-γ on CD11b+Gr-1+ myeloid cell differentiation and function, using a heat-killed Mycobacterium bovis BCG-induced chronic inflammation model. After challenge with heat-killed BCG, two subpopulations of CD11b+Gr-1+ myeloid cells were generated in the mouse spleen. Phenotypical, morphological and functional analysis indicated that the CD11b+Gr-1high Ly6Ghigh Ly6Clow subset was neutrophil-like myeloid-derived inducer cells (N-MDICs), which promoted T cell activation, while the other subset was CD11b+Gr-1low Ly6Gneg Ly6Chigh monocyte-like myeloid-derived suppressor cells (M-MDSCs) that displayed extensive suppressor function. IFN-γ treatment dampened N-MDICs-mediated T cell activation through up-regulating T cell suppressive mediators, reactive oxygen species (ROS) and arginase I. While for M-MDSCs, IFN-γ reduced their suppressing activity by decreasing the arginase activity. Our study provides evidence that IFN-γ balances the over-reactive vs compromised immune response through different regulation of distinct myeloid subsets, and therefore displays significant therapeutic potential for effective immuno-therapy of chronic inflammatory diseases.