Immune Netw.  2017 Oct;17(5):343-351. 10.4110/in.2017.17.5.343.

Plasmacytoid Dendritic Cells Contribute to the Protective Immunity Induced by Intranasal Treatment with Fc-fused Interleukin-7 against Lethal Influenza Virus Infection

• Kang MC
• Park HW
• Choi DH
• Choi YW
• Park Y
• Sung YC
• Lee SW

• KMID: 2400639
• DOI: http://doi.org/10.4110/in.2017.17.5.343

Abstract

Developing a novel vaccine that can be applied against multiple strains of influenza virus is of utmost importance to human health. Previously, we demonstrated that the intranasal introduction of Fc-fused IL-7 (IL-7-mFc), a long-acting cytokine fusion protein, confers long-lasting prophylaxis against multiple strains of influenza A virus (IAV) by inducing the development of lung-resident memory-like T cells, called T(RM)-like cells. Here, we further investigated the mechanisms of IL-7-mFc-mediated protective immunity to IAVs. First, we found that IL-7-mFc treatment augments the accumulation of pulmonary T cells in 2 ways: recruiting blood circulating T cells into the lung and expanding T cells at the lung parenchyma. Second, the blockade of T cell migration from the lymph nodes (LNs) with FTY720 treatment was not required for mounting the protective immunity to IAV with IL-7-mFc, suggesting a more important role of IL-7 in T cells in the lungs. Third, IL-7-mFc treatment also recruited various innate immune cells into the lungs. Among these cells, plasmacytoid dendritic cells (pDCs) play an important role in IL-7-mFc-mediated protective immunity through reducing the immunopathology and increasing IAV-specific cytotoxic T lymphocyte (CTL) responses. In summary, our results show that intranasal treatment with IL-7-mFc modulates pulmonary immune responses to IAV, affecting both innate and adaptive immune cells.

Keyword

Interleukin-7; Fc fusion protein; Orthomyxoviridae; Dendritic cells; T-Lymphocytes

MeSH Terms

Cell Movement
Dendritic Cells*
Fingolimod Hydrochloride
Humans
Influenza A virus
Influenza, Human*
Interleukin-7*
Lung
Lymph Nodes
Lymphocytes
Orthomyxoviridae*
T-Lymphocytes
Fingolimod Hydrochloride
Interleukin-7

Figure

• 

  Figure 1 Effect of FTY720 treatment on the expansion of pulmonary TRM-like cells following the intranasal introduction of IL-7-mFc. Mice (BALB/c, n=6) in each group were treated with PBS or IL-7-mFc i.n. (A-C) Pulmonary CD4 and CD8 T cells were analyzed for the level of CD62L and CD44 at each indicated time point after IL-7-mFc treatment. The number of CD4 and CD8 T cells in the lung (A) and CD62LloCD44high population in each T cell population (B, C) are shown as representative plots and graphs, respectively. (D-F) Mice were treated with IL-7-mFc i.n., and at the same time, they were also treated twice with 60 μg of FTY720 i.p. at 3-day intervals. The absolute number of total pulmonary CD4 and CD8 T cells (D) and the CD62LloCD44high population (F) in each T cell population were analyzed 6 day post-IL-7-mFc treatment. (E) Representative plots for TRM-like cells in the lung are shown. The data are representative of 2 independent experiments and expressed as the mean±standard error of mean. *p<0.05, **p<0.01 by Student's t-test.

• 

  Figure 2 Effect of FTY720 treatment on IL-7-mFc-mediated protection against IAV. (A) Mice (BALB/c, n=6) in each group were treated with PBS or IL-7-mFc i.n. At the same time, some mice were also treated twice with 60 μg of FTY720 at 3-day intervals. Mice were challenged with a lethal dose of H5N2 6 day post-IL-7-mFc treatment. Survival rates are shown. The data are representative of 2 independent experiments. (B) Mice were treated as described in (A) and treated with 200 μg of anti-CD4 mAb at −1, 0, 1, and 3 day post-challenge. The data are representative of 2 independent experiments. **p<0.01 by log-rank test compared with PBS controls, ††p<0.01 by log-rank test comparing the IL-7-mFc and FTY720 groups.

• 

  Figure 3 Role of pDCs in IL-7-mFc-mediated protection against IAV. Mice (BALB/c, n=6) were treated with 200 μg of anti-PDCA-1, anti-CD4 antibody, or IgG control (D-1, D0, D4, D7) after IL-7-mFc treatment and challenge. (A-C) Representative plots and absolute number of pDCs and other myeloid cells in the lung of IL-7-mFc-treated mice measured 9 dpi. (D) Mice were challenged with a lethal dose of H5N2. Weight and survival of the mice were monitored daily. Absolute number of neutrophils (E) in the lung of IL-7-mFc treated mice and inflammatory cytokines and chemokines (F) at 9 dpi were also measured in the BALF. (G) Antigen-specific CD8+ T cell response was assessed by intracellular cytokine staining of IFNγ after HA529–543 stimulation. Results are representative of 2 independent experiment and expressed as the mean±standard error of mean. *p<0.05, **p<0.01, ***p<0.001; ††p<0.01 by log-rank test.

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