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 7

Inhibition of T cell proliferation by MDSCs purified from IAV-infected individuals.

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Inhibition of T cell proliferation by MDSCs purified from IAV-infected i...
CD11b+ cells were bead purified from PBLs derived from either IAV-infected individuals (A–C) or healthy donors (D and E). All donors were bled twice. For donors 1, 2, and 3, the first blood sample was collected before the clinical symptom onset, while the second blood sample was collected within 30–60 days after the acute respiratory illness. Donors 4 and 5 did not have any respiratory illness within the time frame of the collection of the 2 blood samples. Irradiated purified CD11b+ cells were then added to allogenic PBLs and incubated with allogeneic irradiated DCs. Purified CD11b+ cells were either untreated (black bars) or treated with either α-GalCer (100 ng/ml) in the presence of iNKT cells at a MDSC/iNKT ratio of 1:0.25 (white bars) or L-NMMA and NOHA (gray bars). The data are expressed as described in Methods. Addition of either iNKT cells or L-NMMA and NOHA to the alloreactive PBLs in the absence of CD11b+ cells did not affect T cell proliferation (data not shown). The ratio of irradiated DCs to purified irradiated CD11b+ cells was 1:1.