Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant

M Paula Longhi, Christine Trumpfheller, Juliana Idoyaga, Marina Caskey, Ines Matos, Courtney Kluger, Andres M Salazar, Marco Colonna, Ralph M Steinman, M Paula Longhi, Christine Trumpfheller, Juliana Idoyaga, Marina Caskey, Ines Matos, Courtney Kluger, Andres M Salazar, Marco Colonna, Ralph M Steinman

Abstract

Relative to several other toll-like receptor (TLR) agonists, we found polyinosinic:polycytidylic acid (poly IC) to be the most effective adjuvant for Th1 CD4(+) T cell responses to a dendritic cell (DC)-targeted HIV gag protein vaccine in mice. To identify mechanisms for adjuvant action in the intact animal and the polyclonal T cell repertoire, we found poly IC to be the most effective inducer of type I interferon (IFN), which was produced by DEC-205(+) DCs, monocytes, and stromal cells. Antibody blocking or deletion of type I IFN receptor showed that IFN was essential for DC maturation and development of CD4(+) immunity. The IFN-AR receptor was directly required for DCs to respond to poly IC. STAT 1 was also essential, in keeping with the type I IFN requirement, but not type II IFN or IL-12 p40. Induction of type I IFN was mda5 dependent, but DCs additionally used TLR3. In bone marrow chimeras, radioresistant and, likely, nonhematopoietic cells were the main source of IFN, but mda5 was required in both marrow-derived and radioresistant host cells for adaptive responses. Therefore, the adjuvant action of poly IC requires a widespread innate type I IFN response that directly links antigen presentation by DCs to adaptive immunity.

Figures

Figure 1.
Figure 1.
Poly IC is a superior adjuvant to elicit CD4+ T cell immunity. (A) CxB6 F1 mice were primed and boosted 4 wk apart with 5 µg α-DEC-p24 and 50 µg poly IC, 50 µg Pam3cys, 0.5 µg Malp2, 50 µg poly ICLC, 10 µg LPS, 50 µg CpG, or R-848 cream. R-848 cream was applied topically over 5 cm2 on the back of shaved mice. IFN-γ secretion in gated CD3+CD4+ splenic T cells in response to HIV gag p24 peptides was measured 1 wk after boost. (B) As in A, but means ± SD from five (poly IC), three (poly ICLC, R-848, and CpG), and two (Malp-2, Pam3cys, and LPS) experiments, with three mice per group. (C) CxB6 F1 mice were primed and boosted 4 wk apart with 5 µg α-DEC-p24 and 50 µg poly IC. 1 wk after boost, bulk splenocytes were stimulated with gag p24 peptide mix or control peptide mix for 3 d. The concentrations of the indicated cytokines and chemokines were measured in cell culture supernatants by luminex. Samples were acquired in duplicate and analyzed by ELISA. Bars represent the mean ± SD from two experiments (six mice total). (D) Mice were immunized as in A. 1 wk after boost, gag-specific antibodies in serum samples were measured by ELISA. Data are given as OD mean ± SD from two independent experiments (five mice total).
Figure 2.
Figure 2.
Induction of inflammatory cytokines in the serum by TLR ligands. Mice were treated i.p. with 50 µg poly IC, 50 µg Pam3cys, 0.5 µg Malp2, 10 µg LPS, 50 µg poly ICLC, 50 µg CpG, and 5 cm2 of 0.2% R-848 cream. IL-6, TNF-α, IL-12p40, IFN-α, IFN-β, and IFN-γ were analyzed in serum at different time points (means of four mice). Error bars indicate the mean ± SD. Data are representative of two similar independent experiments.
Figure 3.
Figure 3.
Type I IFN signaling controls DC maturation. (A) 1 h after 100 µg of anti-IFAR1 blocking antibody or isotype control, mice were stimulated with 50 µg poly IC for 12 h and analyzed for cell surface MHC-II, CD86, and CD40 on DEC+ and DEC− DCs. (B) As in A, but graded numbers of fixed splenic DCs from BALB/C mice were added for 5 d to 2 × 105 allogeneic C57BL/6 T cells. T cell proliferation was detected by CFSE dilution of CD3+ cells. Data are representative of three experiments.
Figure 4.
Figure 4.
Direct type I IFN signaling of DCs is required for their maturation. Mixed bone marrow chimeras were prepared with a 50:50 mixture of bone marrow from WT (CD45.2−) and IFNAR−/− (CD45.2+) mice. (A) Gating strategy for WT (CD45.2−) and IFNAR−/− (CD45.2+) DCs 4–6 wk after chimerism. (B) The chimeras were stimulated with 50 µg poly IC or PBS for 12 h. Expression of CD86, MHC-II, and CD40 on WT and IFNAR−/− DCs, was analyzed by FACS. Arrows show increased up-regulation of costimulatory molecules in IFNAR−/− DCs. (C) The chimeras were stimulated as in B. After CD11c enrichment, WT and IFNAR−/− CD11chi were FACS sorted as in A. Graded numbers of fixed B6.WT or B6.IFNAR−/− splenic DCs were added for 5 d to 2 × 105 allogeneic Balb/C T cells. T cell proliferation was detected by CFSE dilution of CD3+ cells. Cells numbers are indicated as 103. Data are representative of two similar independent experiments.
Figure 5.
Figure 5.
NK cells are major producers of IFN-γ after poly IC. Mice were injected i.p. with 50 µg poly-IC or PBS. After 2 h, spleens were collected and a single cell suspension of splenocytes was incubated with 10 µg/ml BFA for 3 h before intracellular staining for IFN-γ. (A) Five color flow cytometry to identify IFN-γ–positive splenocytes. (B) As in A, but production of IFN-γ by NK cells gated as CD3− DX5+ cells. Means ± SD of four experiments. (C) Highly purified CD3− DX5+ NK cells. 3 × 105 cells/well were stimulated with 50 µg/ml poly IC or, as a positive control, a combination of rIL-12 and rIL-15. After 12 h, IFN-γ in culture supernatants was detected by ELISA. Means ± SD of three independent experiments are shown. (D) Mice were injected with poly IC and anti-IFAR1 blocking antibody or isotype control. Production of IFN-γ was detected by intracellular staining. Mean ± SD from three experiments is shown.
Figure 6.
Figure 6.
Production of IFN-β by multiple cell types. (A) Splenocytes from WT mice were depleted with Ter119−, CD3−, and CD19− biotinylated antibodies using streptavidin magnetic beads before cell sorting. For monocytes, macrophages, and granulocytes, splenocytes were additionally depleted of DX5+ cells. cDCs (CD3−DX5−CD11chiCD8− and CD8+DEC205+), pDCs (CD3−DX5−CD11clowB220+), NK cells (CD3−DX5+), macrophages (CD11blowF4/80+), monocytes (CD11bhiCD115+), and granulocytes (CD11bhiLy6G+) were sorted based on their expression of specific markers (see text). Numbers 1–6 indicate the different cell types sorted. (B) Highly purified cells were plated at 3 × 105 cells/well in a round-bottomed 96-well plate and incubated with 50 µg/ml poly IC or medium alone. Splenic stromal cells, obtained as described in the Materials and methods, were plated at 5 × 104 cells/well in a 48-well plate. Supernatants were collected after 12 h and production of Type I IFN was detected by ELISA. (C) As in B, DEC+ DCs, monocytes, stromal cells from WT, TLR3−, and mda5-deficient mice were stimulated in vitro with 50 µg/ml poly IC or medium alone. (D) WT and mda5−/− mice were lethally irradiated and injected with bone marrow cells from WT or mda5−/− mice. After 6 wk, chimeras were injected with 50 µg poly IC. Serum was collected 6 h later and analyzed by Type I IFN ELISA kit. Error bars show the means ± SD from at least two experiments. ND, not detectable.
Figure 7.
Figure 7.
The adjuvant role of poly IC is dependent on type I IFNs and independent of IL-12 p40. (A) CxB6 F1 mice were injected i.p. with 5 µg α-DEC-p24 or 10 µg gag-p41 and 50 µg poly IC together with anti-IFNAR1 or isotype control. Mice were boosted with the same conditions at 4 wk. 1 wk later, HIV gag-specific CD3+ CD4+ splenic T cells were analyzed for IFN-γ. (B–E) As in A, the percentage of CD3+ CD4+ T cells producing IFN-γ was measured in WT, IFNAR−/−, STAT-1−/−, IFN-γR−/−, and IL-12 p40−/− immunized mice, respectively. Means ± SD are shown of two independent experiments with a total of six mice. ***, P = 0.001.
Figure 8.
Figure 8.
Both hematopoietic and nonhematopoietic cells contribute to the adjuvant effect of poly IC. (A) Gag p24-specific CD4+ T cell responses were evaluated in bone marrow chimeras. WT and double TLR3.mda5−/− mice were lethally irradiated and injected with bone marrow cells from WT or deficient mice. After 6 wk, chimeras were primed and boosted 4 wk apart with 5 µg α-DEC-p24 and 50 µg poly IC. After 1 wk, HIV gag-specific CD3+CD4+ splenic T cells were analyzed for IFN-γ secretion. Means ± SD from two experiments are shown; n = 6. (B) Chimerism was assessed by expression of mda5 on CD11c+ splenic cells. ***, P = 0.001.

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