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 3

The crosstalk between iNKT and MDSCs is CD1d and CD40 dependent.

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The crosstalk between iNKT and MDSCs is CD1d and CD40 dependent. (A) Los...
(A) Loss of ARG1 and NOS2 activity in α-GalCer–pulsed MDSCs incubated with BM-derived iNKT cells. MDSCs were treated with α-GalCer in the presence of iNKT cells and collected at different time points. ARG1 and NOS2 activities were measured using a colorimetric assay to evaluate urea and nitrate/nitrite release, respectively (17, 18). An ELISA was used to evaluate IL-12p40 production. Values are shown as a percentage relative to time point 0. The maximum amount of urea released by untreated MDSCs (1 × 106) was 91.7 μg. The maximum amount of NO2– and NO3– measured in the supernatant of untreated MDSCs was 120 μM. The maximum amount of IL-12p40 was 200 ng/ml. (B) Incubating α-GalCer–pulsed MDSCs with BM-derived iNKT cells abolishes their suppressive function. CFSE-labeled OT-I cell proliferation was analyzed in the presence (red) or absence (green) of MDSCs derived from WT, Jα18–/–, or CD1d–/– mice. MDSCs were left untreated or pulsed with α-GalCer. Proliferation of OT-I cells without SIINFEKL peptide is superimposed in all panels (black). (C) The effect of iNKT cells on α-GalCer–pulsed MDSCs is CD40 dependent. CFSE-labeled OT-I proliferation was analyzed in the presence (red) or absence (green) of MDSCs derived from WT, CD40–/–, or CD40L–/– mice. MDSCs were left untreated or pulsed with α-GalCer. To assess the role of the CD40 molecules, BM-derived MDSCs were treated with anti–CD40 agonist Ab for 48 hours. Proliferation of CFSE-labeled OT-I cells without SIINFEKL peptide is superimposed in all panels (black).