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 1

Adoptive transfer of iNKT cells mediates protection from lethal doses of PR8.

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Adoptive transfer of iNKT cells mediates protection from lethal doses of...
WT, Jα18–/–, and CD1d–/– mice (n = 8/group) were injected intranasally with PR8 (3 × 104 PFU/mouse). Liver-purified iNKT cells were adoptively transferred i.v. into Jα18–/– (Jα18–/– + iNKT) and CD1d–/– (CD1d–/– + iNKT) mice 1 day after infection. (A) Increased mortality of Jα18–/– mice following PR8 infection is prevented by the adoptive transfer of iNKT cells. Survival rate is shown as the percentage of live mice at different time points after the infection. Data are representative of 5 separate experiments. (B) PR8 titer in Jα18–/– mice is reduced by the adoptive transfer of iNKT cells. Lung homogenates from PR8-infected mice were assayed for number of PFU 6 days after infection. Results of statistical analyses, performed using Student’s t test, are shown. (C) Total number of NP366–374–specific CTLs in PR8-infected Jα18–/– mice is restored by the adoptive transfer of iNKT cells. The number of NP366–374–specific CTLs represents the average (±SD) of results obtained in n = 8 mice/group. Results of statistical analyses, performed using Student’s t test, are shown. (D) Anti-PR8 Ab titers in PR8-infected Jα18–/– mice are restored by the adoptive transfer of iNKT cells. The titer of anti-PR8–specific IgG was measured 6 days after infection.