Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans
Carmela De Santo, … , Maria Zambon, Vincenzo Cerundolo
Carmela De Santo, … , Maria Zambon, Vincenzo Cerundolo
Published November 13, 2008
Citation Information: J Clin Invest. 2008;118(12):4036-4048. https://doi.org/10.1172/JCI36264.
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Research Article

Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans

Abstract

Infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection.

Authors

Carmela De Santo, Mariolina Salio, S. Hajar Masri, Laurel Yong-Hwa Lee, Tao Dong, Anneliese O. Speak, Stefan Porubsky, Sarah Booth, Natacha Veerapen, Gurdyal S. Besra, Hermann-Josef Gröne, Frances M. Platt, Maria Zambon, Vincenzo Cerundolo

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Figure 5

TLR-L–treated MDSCs derived from Hexβ–/– mice fail to stimulate iNKT cells.

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Infection of MDSCs with PR8 fosters their ability to activate iNKT cells...
(A) iNKT cells derived from WT mice fail to produce IFN-γ when incubated with TLR-L–matured MDSCs derived from Hexβ–/– mice. IFN-γ secretion by iNKT cells derived from WT mice, coincubated with TLR-L–matured MDSCs derived from Hexβ–/– or iGb3S–/– mice. Different protocols are indicated. (B) CpG-treated Hexβ–/– MDSCs fail to foster the crosstalk between iNKT cells and MDSCs. CFSE-labeled OT-I proliferation in the presence of TLR-L–treated MDSCs derived from either Hexβ–/– or iGb3S–/– mice is shown. BM-derived Hexβ–/– and iGb3S–/– MDSCs were treated with CpG in the presence or absence of blocking anti-CD1d Ab. Proliferation of OT-I cells in the presence (red) or absence (green) of MDSCs is shown. Proliferation without the SIINFEKL peptide (black) is superimposed in all panels. (C) Inhibition of GSL biosynthesis in TLR-L–matured MDSCs reduces iNKT cell activation. MDSCs derived from WT mice were incubated with either poly I:C or CpG and then treated with increasing concentrations of N-butyldeoxygalactonojirimycin (NB-DGJ). MDSCs were incubated with iNKT cells for 24 hours and tested for their effect on OT-I proliferation (see Methods). Addition of NB-DGJ to OT-I splenocytes in the absence of MDSCs did not affect OT-I proliferation (data not shown). Proliferation of unpulsed OT-I splenocytes in the absence of MDSCs is shown (dark gray). Treatment of MDSCs with TLR-L (light gray bars) relieves CFSE-labeled OT-I proliferation, as compared with the lack of OT-I proliferation observed after addition of untreated MDSCs. In contrast, combined treatment of MDSCs with either CpG (black bars) or poly I:C (white bars) plus increasing doses of NB-DGJ reduces OT-I proliferation.