Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy

Abstract

Pleural tuberculosis (TB) is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC) has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF) in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2), but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection.

Human Monocytic Suppressive Cells Promote Replication of Mycobacterium tuberculosis and Alter Stability of in vitro Generated Granulomas

“…This may indicate that the MDSCs do not alter antigen specific cytokine release, or alternatively that sources of these cytokines inside in vitro generated granuloma-like structures were unresponsive to MDSCs. While we measured soluble TNF-α aiming to ascertain a possible role in IVGLS stability, a role for transmembrane TNF in human MDSCs, including suppression of lymphocytes, as demonstrated in mice ( 22 ), cannot be excluded. Irrespective of their suppressive mechanisms, human MDSCs did not modify abundances of TNF-α in IVGLSs.…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…If the process of the maturation of myeloid precursors was abrogated at different stages by some cytokines like TNF‐α, MDSCs will be generated eventually such pathological conditions as cancer (Fig. ) . The frequency of MDSCs was found to be closely associated with the progression and clinical staging in some cancer patients and tumor bearing mice.…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…TNF neutralization exerts the same effect, indicating that TNF signaling is important for the accumulation of MDSCs. In addition, during BCG‐induced pleurisy, the interaction of TNFR2 and tmTNF is required for T cell suppression mediated by MDSCs . Depletion of MDSCs in different cancer models has also been carried out by inhibiting their proliferation, expansion, and activation .…”

“…115 Conditional mouse models, such as the "DTR-target gene mouse", are useful for depleting more specific cell types, such as FoxP3 + Treg cells. 116 Due to the lack of MDSC-specific surface molecules, it is virtually impossible to design depletion strategies to specifically target MDSCs ( 121 Depletion of MDSCs in different cancer models has also been carried out by inhibiting their proliferation, expansion, and activation. [122][123][124] Moreover, "peptibodies" have been developed to specifically deplete MDSCs, 125 and have been shown to be effective in different cancer models.…”