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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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 6

Inhibition of alloreactive T cell proliferation by human MDSCs can be rescued by iNKT cells.

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Inhibition of alloreactive T cell proliferation by human MDSCs can be re...
(A) Healthy donors’ GM-CSF–differentiated MDSCs have MLR-suppressive activity, which can be blocked by the addition of NOHA and L-NMMA. The data are expressed as described in Methods. Addition of NOHA and L-NMMA to the MLR in the absence of MDSCs does not affect PBL proliferation (data not shown). The ratio of DCs to human GM-CSF–treated MDSCs is shown. (B) PR8 infection of healthy donors’ GM-CSF–treated MDSCs rescues MLR proliferation. Human GM-CSF–treated MDSCs were left untreated (black bars) or infected with PR8 and cocultured in the presence (gray bars) or absence (white bars) of iNKT cells (2.5 × 104) for 24 hours. After irradiation, PR8-infected and uninfected MDSCs were added to the MLR. The data are expressed as described in Methods. The ratio of DCs to human MDSCs used is shown. Results of statistical analyses, performed using Student’s t test, are shown. (C) TLR-L incubation of healthy donors’ GM-CSF–differentiated MDSCs rescues T cell proliferation. Human GM-CSF–treated MDSCs were treated with LPS (10 μg/ml), R848 (5 μg/ml), poly I:C (10 μg/ml), or α-GalCer (100 ng/ml) and cocultured in the presence (white bars) or absence (black bars) of iNKT cells for 24 hours. The data are expressed as described in Methods. The ratio of DCs to human GM-CSF–treated MDSCs used was 1:1.