Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans
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
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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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 2

Adoptive transfer of iNKT cells reduces PR8-induced MDSC expansion.

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Adoptive transfer of iNKT cells reduces PR8-induced MDSC expansion. (A) ...
(A) iNKT cells adoptively transferred into PR8-infected Jα18–/– mice reduced the total number of lung MDSCs. PR8-infected WT, Jα18–/–, and CD1d–/– mice were injected with iNKT cells. Lung homogenates were stained with CD11b and Gr-1 Abs. (B) Injection of sublethal doses of PR8 (3 × 102 PFU) reduces the total numbers of lung MDSCs. (C) Adoptive transfer of iNKT cells reduces in vitro suppressive activity of PR8-induced MDSCs. MDSCs were purified from lungs of PR8-infected mice and cocultured with CFSE-labeled OT-I splenocytes. (D) The suppressive activity of MDSCs from PR8-infected mice is reduced by treatment with anti–CD40 agonist Ab and NOS2 and ARG1 inhibitors. Lung-purified MDSCs were left untreated (black bars) or treated in vitro with either anti–CD40 agonist Ab (white bars) or with NG-monomethyl-l-arginine (L-NMMA) and NOHA (light gray bars) and then added to OT-I splenocytes. Proliferation of unpulsed OT-I splenocytes in the absence of MDSCs is shown (dark gray bars). (E) Adoptive transfer of MDSCs from infected mice suppresses the expansion of UTY246–254–specific CD8+ T cell responses. UTY246–254 CTL responses were assessed in vaccinated mice injected with MDSCs from PR8-infected mice (see Methods). H-2Db/UTY246–254 tetramer (UTY246–254Db tetramer) versus CD8 dot plots are shown for gated propidium iodide–negative lymphocytes, and the percentage of cells staining positively with the tetramers is indicated. In A–E, data represent the average ± SD of n = 5 mice/group, and results of statistical analyses, performed using Student’s t test, are shown.