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Type I IFN Signaling on Both B and CD4 T Cells Is Required for Protective Antibody Response to Adenovirus¹

Jiangao Zhu^*, Xiaopei Huang^* and Yiping Yang^2,*,

^* Department of Medicine, Division of Medical Oncology, and Department of Immunology, Duke University Medical Center, Durham, NC 27710

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Recombinant adenoviruses have been used as vehicles for gene therapy as well as vaccination against infectious diseases and cancer. Efficient activation of host B cell response to adenoviral vectors that leads to the generation of protective, neutralizing Ab, represents a major barrier for gene therapy, but an attractive feature for vaccine development. What regulate(s) potent B cell response to adenoviral vectors remains incompletely defined. In this study, we showed that type I IFNs induced upon adenoviral infection are critical for multiple stages of adaptive B cell response to adenovirus including early B cell activation, germinal center formation, Ig isotype switching as well as plasma cell differentiation. We further demonstrated that although type I IFN signaling on dendritic cells was important for the production of virus-specific IgM, the generation of protective neutralizing Ab critically depended on type I IFN signaling on both CD4 T and B cells. The results may suggest potential strategies for improving adenovirus-mediated gene therapy in vivo and/or the design of effective vaccines for cancer and infectious diseases.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Replication-defective adenoviral vectors have been used widely in gene therapy applications due to their high efficiency of transduction into a wide variety of nondividing cells in vivo (1). However, significant problems of attendant host innate and adaptive immune responses have limited the use of adenoviral vectors for gene therapy because of the concerns for their safety and efficacy in vivo (1, 2). Interestingly, the inherent immunogenicity of adenoviral vectors has led to their development as potential vaccine vehicles for infectious diseases such as HIV and malaria, and cancer (3, 4). Among host immune responses, efficient generation of neutralizing Abs to the vectors and transgenes represents a major barrier for gene therapy (5, 6, 7), but a desirable feature for vaccine development (3, 4). Although studies have shown that Ab response to adenoviral vectors is CD4 Th cell dependent (6, 8), it remains to be defined whether other signals, particularly innate immune cytokines, also contribute to potent humoral immune response upon adenoviral infection. Thus, further elucidation of these potential signals required for efficient B cell response may help us design effective vaccines as well as strategies to allow repeated administration of the vector for gene therapy in vivo.

Among many innate immune cytokines, type I IFNs that are produced by host cells early after viral infection have emerged as a critical player in anti-viral immune responses (9). They are a family of cytokines that constitute 13 IFN- subtypes and one IFN- in mice and humans (10). All type I IFNs appear to signal through a heterodimeric receptor composed of two subunits, IFN- receptor 1 (IFNAR1) and IFNAR2 (9). It has been well known that type I IFNs have direct antiviral activities through suppression of viral replication and induction of cell death in infected cells by inhibiting RNA and protein synthesis (11, 12). Recent studies have also suggested a critical role for type I IFNs in the regulation of immune responses (9). It has been shown that efficient activation of NK cells and macrophages is dependent on type I IFNs (13). In addition, type I IFNs also promote adaptive T and B cell responses in a variety of models (10).

In this study, we found that type I IFNs were also rapidly induced upon adenoviral infection in vivo. Using mice deficient for type I IFN receptor (IFNR^–/–), we showed that type I IFNs were critical for the activation of subsequent adaptive B cell response to adenoviral vectors. We also identified that the requirement for type I IFNs occurred at multiple stages of B cell response including early B cell activation, generation of germinal center B cells as well as plasma cell differentiation. We further demonstrated that the production of virus-specific IgM was dependent on type I IFN signaling on dendritic cells (DCs),³ whereas type I IFN signaling directly on both B cells and CD4 Th cells are necessary for Ig isotype switching and the formation of protective, neutralizing Ab response to adenoviral vectors. Thus, type I IFN signaling on different immune cell type has differential effects on B cell response to adenoviral infection.

	Materials and Methods

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Mice

IFNR^–/– mice (11) on 129/Sv background (H-2^b) were obtained from B & K Universal, and their normal control 129/Sv mice were purchased from Charles River Laboratories. RAG-2 deficient (RAG-2^–/–) 129/Sv mice were purchased from Taconic Farms. Groups of 6- to 8-wk-old mice were selected for this study. All experiments involving the use of mice were done in accordance with protocols approved by the Animal Care and Use Committee of Duke University.

Recombinant adenoviruses

Recombinant E1-deleted adenovirus encoding lacZ (Ad-lacZ) under the control of the CMV promoter was generated by homologous recombination in Escherichia coli as described (14). Virus was grown in 293 cells, purified by two rounds of CsCl density centrifugation and desalted by gel filtration through Sephadex G-25 column (PD-10 column; Amersham Bioscience) as described (15). The titer of virus was determined as PFU by plaque forming assay on 293 cells (16).

A total of 2 x 10⁹ PFU Ad-lacZ in 0.1 ml of PBS was injected into mice i.v. as described (15). Mice were sacrificed at indicated time points for histological and/or immunological assays. All animals that received recombinant virus survived to the time of necropsy.

Type I IFN measurement by ELISA

The detection of IFN- and IFN- in the serum was measured by ELISA according to manufacturer’s standard protocols. IFN- and IFN- ELISA kits were obtained from PBL Biomedical Laboratories.

Neutralizing Ab assay

Neutralizing Ab titer in the serum was measured as described (6). In brief, serum samples were incubated at 56°C for 30 min and then diluted in DMEM in 2-fold steps starting from 1/20 or 1/50. Each serum dilution (100 µl) was mixed with Ad-lacZ (2 x 10⁶ PFU in 20 µl), incubated for 1 h at 37°C, and applied to 80% confluent HeLa cells in 96-well plates (2 x 10⁴ cells per well). After 60 min of incubation at 37°C, 100 µl of DMEM containing 20% FBS was added to each well. Cells were fixed and analyzed for lacZ expression by 5-bromo-4-chloro-3-indolyl -D-galactoside staining on the following day as described (6). All of the cells stained blue in the absence of serum samples. The titer of neutralizing Ab for each sample was reported as the highest dilution with which <50% of cells stained blue.

Adenovirus-specific Ab isotyping by ELISA

Adenovirus-specific Ab isotypes were determined by ELISA as described with some modifications (6). In brief, 96-well plates (Nunc-Immuno Modules) were coated overnight at 4°C with 100 µl of buffer (0.1 M NaHCO₃, pH 9.6) containing 4 x 10⁷ PFU of Ad-lacZ. Wells were then successively washed three times with PBS/0.05% Tween 20, saturated with 200 µl of 10% FBS in PBS, rinsed three times in PBS/0.05% Tween 20 and incubated with serial-diluted serum samples for 2 h at room temperature. Wells were then washed five times with PBS/0.05% Tween 20 and 100 µl of biotin-conjugated goat anti-mouse IgM, IgG1, IgG2a, IgG2b, or IgG3 (dilution 1/5000; Southern Biotechnology Associates) were added. After incubation for 1 h, wells were washed and added with 100 µl of HRP-coupled streptavidin (dilution 1/1000; BD Biosciences). Finally, 100 µl per well of the substrate solution (TMB; BD Biosciences) were added, and the substrate conversion was stopped by the addition of 100 µl per well of 2 N HCl. Absorbance was measured at 450 nm. Results are expressed as reciprocal endpoint titers as described (17).

Flow cytometry

The following Abs were used for characterization of B cells and other cell types: anti-CD19, anti-GL7, anti-CD69, anti-CD86, and anti-CD4, all of which were purchased from BD Biosciences. FACScan (BD Biosciences) was used for flow cytometry event collection and events were analyzed with CELLQuest software (BD Biosciences).

Immunohistochemistry

Frozen sections (5 µm) were fixed with acetone and stained with biotinylated peanut agglutinin (Vector Laboratories) at 15 µg/ml for 50 min. After three washes with PBS, sections were incubated with HRP-avidin-biotin complex (Vector Laboratories) for 30 min. Sections were then treated for 5 min with a peroxidase diaminobenzidine solution (Vector Laboratories) and counterstained with Meyer’s hematoxylin.

Real-time quantitative PCR

Total RNA was isolated from purified cells using TRIzol reagent (Invitrogen Life Technologies). cDNA was synthesized using reverse transcription kit (Promega). Real-time PCR was performed using an iCycler instrument (Bio-Rad) to measure SyBR green incorporation. The following primer sets were used: Blimp-1, 5'-TGT GTG GTA TTG TCG GGA CT-3', 5'-TGA AGG GTG AAA TGT TGG AA-3'; Bcl-6, 5'-AAG GCC AGT GAA GCA GAA AT-3', 5'-GGA TAA GAG GCT GGT GGT GT-3'. Relative amounts of mRNA were normalized to hypoxanthine phosphoribosyltransferase RNA levels within each sample.

Adoptive transfer experiments

For DC reconstitution experiments, splenic DC isolation was performed as described (18). After perfusion with Liberase CI (Roche Biochemicals), single-cell suspensions were subjected to 30% BSA gradient, and the interface DC fraction was collected and stained with anti-CD11c-PE followed by anti-PE-microbeads (Miltenyi Biotec). CD11c⁺ DCs were purified by FACS sorting after enrichment by microbeads; 1 x 10⁶ of splenic CD11c⁺ DCs (>95% purity) purified from wild-type (WT) or IFNR^–/– 129/Sv mice were transferred into IFNR^–/– mice, which were subsequently infected with adenovirus as described.

For reconstitution of CD4 T cells and B cells, CD4⁺ T cells and B220⁺ B cells were purified from the spleen of naive 129/Sv or IFNR^–/– mice by double selection with CD4 microbeads or B220 microbeads. Cell purity was assessed by FACS analysis, and 5 x 10⁶ of purified CD4⁺ T cells (>95% of purity) were cotransferred into RAG-2^–/– mice with 1 x 10⁷ B220⁺ B cells (cell purity >99%) i.v. One week later, mice were injected with Ad-lacZ and sacrificed at indicated time points for histological and/or immunological assays.

Statistical analysis

Results are expressed as mean ± SD. Differences between groups were examined for statistical significance using Student’s t test.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Induction of type I IFNs upon adenoviral infection in vivo

To determine whether type I IFNs play a role in B cell response to adenoviral vectors, we first examined whether type I IFNs could be induced upon adenoviral infection in vivo. WT 129/Sv mice were injected with 2 x 10⁹ PFU of Ad-lacZ i.v., and sera were harvested and assayed for IFN- and IFN- 1, 6, 12, or 18 h later. We found that the levels of IFN- (Fig. 1A) and IFN- (Fig. 1B) increased over time and peaked at 12 h after infection. Consistent with the previous observations (19, 20), these results indicate that type I IFNs can be induced rapidly upon adenoviral infection in vivo.

View larger version (10K): [in this window] [in a new window]   FIGURE 1. Rapid induction of type I IFNs upon adenoviral infection in vivo. 129/Sv mice were injected with Ad-lacZ i.v. at a dose of 2 x 109 PFU. 0, 1, 6, 12, or 18 h later, sera were measured for IFN- (A) and IFN- (B) by ELISA. Representative data of three independent experiments are shown.

We next investigated whether adenovirus-induced type I IFNs influenced adaptive B cell response to adenoviral infection. To address this question, mice deficient for type I IFN receptor (IFNR^–/–) were tested for their ability to generate adenovirus-specific Ab response upon adenoviral infection in vivo. WT or IFNR^–/– mice were injected with 2 x 10⁹ PFU of Ad-lacZ i.v., and serum samples were harvested 10 or 21 days later and assayed for the presence of neutralizing Ab to adenoviral vectors as well as virus-specific Ig isotypes by ELISA. Sera from WT mice infected with Ad-lacZ were found to contain high titers of neutralizing Ab compared with that from uninfected WT mice (Fig. 2A). However, neutralizing Ab titers were significantly diminished in Ad-lacZ-infected IFNR^–/– mice (p < 0.001, Fig. 2A). Similarly, we found that adenovirus-specific IgM (p < 0.01, Fig. 2B), IgG1 (p < 0.01, Fig. 2C), IgG2a (p < 0.001, Fig. 2D), IgG2b (p < 0.001, Fig. 2E) and IgG3 (p < 0.001, Fig. 2F) titers were also significantly reduced in IFNR^–/– mice compared with the WT mice. Thus, the formation of neutralizing Ab to adenoviral vectors and virus-specific Ig isotypes in vivo is critically dependent on an intact type I IFN signaling pathway.

View larger version (19K): [in this window] [in a new window]   FIGURE 2. Type I IFNs are critical for the formation of neutralizing Abs and virus-specific Ig isotypes. WT or IFNR–/– 129/Sv mice were injected with 2 x 109 PFU of Ad-lacZ in 100 µl of PBS (Ad) or PBS only (Control) i.v. Serum samples were harvested 21 days later for the measurement of neutralizing Ab titers to adenoviral vectors (A). Day 10 serum samples from adenovirus-infected mice were also analyzed for virus-specific IgM (B), and day 21 samples were analyzed for virus-specific IgG1 (C), IgG2a (D), IgG2b (E), and IgG3 (F) by ELISA. Data shown are representative of four independent experiments.

It is well known that B cell response to antigenic stimulation is a multistep process (21). We therefore studied which stage(s) of B cell response is regulated by type I IFNs. We first looked at the role of type I IFNs in early B cell activation; 2 x 10⁹ PFU of Ad-lacZ were injected i.v. into WT or IFNR^–/– mice. Twenty-four hours later, activation of splenic CD19⁺ B cells were examined for their expression of CD69 and CD86. In WT mice, adenoviral infection up-regulated the expression of CD69 and CD86 compared with the uninfected control mice (Fig. 3). By contrast, up-regulation of CD69 or CD86 expression was not detected in IFNR^–/– mice (Fig. 3). This result indicates that type I IFN signaling is required for early B cell activation.

View larger version (34K): [in this window] [in a new window]   FIGURE 3. Type I IFN signaling is required for early B cell activation. WT or IFNR–/– mice were injected with 2 x 109 PFU of Ad-lacZ in 100 µl of PBS (Ad) or PBS only (Control) i.v.; 24 h later, splenocytes were stained with anti-CD19 and anti-CD69, or anti-CD86 and subjected to FACS. The events were gated on CD19+ B cells. Data shown are representative of three independent experiments.

View larger version (58K): [in this window] [in a new window]   FIGURE 4. Type I IFNs promote germinal center formation. WT or IFNR–/– mice were injected with 2 x 109 PFU of Ad-lacZ in 100 µl of PBS (Ad) or PBS only (Control) i.v. A, Ten days later, splenocytes were stained with anti-CD19 and anti-GL7, and subjected to FACS. The percentages of CD19+GL7+ germinal center B cells are indicated. B, Ten days after infusion of virus, frozen spleen sections were stained with PNA (brown) and counterstained with hematoxylin. Data shown are representative of four independent experiments.

View larger version (10K): [in this window] [in a new window]   FIGURE 5. Regulation of Blimp-1 and Bcl-6 expression in germinal center B cells by type I IFNs. WT or IFNR–/– mice were injected with Ad-lacZ i.v., and 10 days later, CD19+GL7+ germinal center B cells were purified by FACS sorting. Total RNA was then isolated from the purified cells and subjected to real-time quantitative PCR to measure the expression of Blimp-1 or Bcl-6. Data are presented as normalized Blimp-1 or Bcl-6 mRNA abundance to hypoxanthine phosphoribosyltransferase. Data shown are representative of three independent experiments.

Type I IFN signaling on DCs enhances the production of virus-specific IgM but not the formation of neutralizing Ab

Previous studies in a model of B cell response to soluble Ags have suggested that type I IFNs enhance Ab response to a soluble Ag by stimulating DCs (17). To determine whether the same is true in B cell response to adenoviral infection, splenic DCs purified from WT or IFNR^–/– mice by FACS sorting were transferred into IFNR^–/– mice followed by infusion of Ad-lacZ i.v. Serum samples were measured for virus-specific IgM 10 days later, and IgG2a, IgG2b, and neutralizing Ab 21 days later. No significant difference in virus-specific Ig titers was observed in IFNR^–/– mice treated with IFNR^–/– DCs from IFNR^–/– mice (Fig. 6). By contrast, IFNR^–/– mice injected with WT DCs showed a significant (p < 0.01) increase over IFNR^–/– mice in virus-specific IgM titers to a level comparable to those of WT mice (Fig. 6A). However, reconstitution of IFNR^–/– mice with WT DCs did not result in an enhancement of virus-specific IgG2a (Fig. 6B), IgG2b (Fig. 6C) or neutralizing Ab titers (Fig. 6D). These results suggest that type I IFN signaling through DCs only promotes the production of virus-specific IgM, but not Ig isotype switching or the formation of neutralizing Ab to adenovirus.

View larger version (16K): [in this window] [in a new window]   FIGURE 6. Type I IFN signaling on DCs only enhances the production of virus-specific IgM. WT or IFNR–/– mice, or IFNR–/– mice reconstituted with FACS-purified splenic CD11c+ DCs from the WT mice (plus WT DC) or IFNR–/– mice (plus IFNR–/– DC) were subsequently injected with 2 x 109 PFU of Ad-lacZ i.v. Serum samples were harvested 10 days later for the measurement of virus-specific IgM (A), or 21 days later for the measurement of virus-specific IgG2a (B) and IgG2b (C) by ELISA as well as neutralizing Ab titers to adenoviral vectors (D). Data shown are representative of three independent experiments.

We next investigated whether type I IFN signaling directly on B cells is required for Ig isotype switching and the formation of protective neutralizing Ab. Because B cell response to adenovirus is Th dependent (6, 8), we also looked at the effect of type I IFN signaling through CD4 T cells. To address these questions, we designed an adoptive transfer system in which type I IFN signaling was defective on CD4 T cells, B cells or both. Purified WT or IFNR^–/– B cells were transferred into RAG-2^–/– mice along with purified WT or IFNR^–/– CD4 T cells. Seven days later, splenocytes were analyzed for homing of CD4 T cells and B cells. Equivalent homing and survival of the transferred cells was detected in all groups (Fig. 7A). Furthermore, the percentages of CD4 T cells and B cells among splenocytes and their absolute numbers were comparable to those in naive WT mice (data not shown). Mice were then infected with Ad-lacZ, and sera were harvested 10 days later for IgM measurement and 21 days later for IgG2a, IgG2b, as well as neutralizing Ab titers. No significant difference in IgM titers was detected in mice that received IFNR^–/– CD4 T cells, IFNR^–/– B cells, or both compared with those received WT CD4 T cells and WT B cells (Fig. 7B), suggesting type I IFN signaling on B cells or CD4 T cells was not required for IgM production, which supports that type I IFN signaling on DCs was sufficient for IgM production (Fig. 6A). By contrast, significant reduction in IgG2a (p < 0.01, Fig. 7C), IgG2b (p < 0.01, Fig. 7D) and neutralizing Ab (p < 0.01, Fig. 7E) titers was observed in mice transferred with either IFNR^–/– CD4 T cells or IFNR^–/– B cells. Furthermore, a greater degree of reduction in Ab titers was detected in mice received both IFNR^–/– CD4 T cells and IFNR^–/– B cells. These results suggest that type I IFN signaling directly on both CD4 T cells and B cells are required for efficient production of neutralizing Ab as well as Ig isotype switching.

View larger version (23K): [in this window] [in a new window]   FIGURE 7. Type I IFN signaling on both B and CD4 T cells is required for Ig isotype switching and formation of protective neutralizing Ab. Purified WT or IFNR–/– B cells were transferred into RAG-2–/– mice along with purified WT or IFNR–/– CD4 T cells. A, 7 days later, splenocytes from mouse groups that received different combinations of CD4+ T cells CD19+ B cells, were stained with anti-CD19 and anti-CD4, and subjected to FACS analysis. Percentages of CD19+ B cells and CD4+ T cells among total splenocytes are indicated. Mice were then infected with Ad-lacZ, and sera were harvested 10 days later for the measurement of virus-specific IgM (B), or 21 days later for virus-specific IgG2a (C), IgG2b (D), as well as neutralizing Ab titers (E). Data shown are representative of three independent experiments.

	Discussion

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Although type I IFNs have been closely associated with direct antiviral responses (26), recent studies have also revealed type I IFNs as a regulator for innate and adaptive immunity including B cell responses (9, 10). In vitro, type I IFNs exhibit both stimulatory and inhibitory effects on B cell proliferation and Ig production (27, 28, 29). However, recent in vivo data have shown that type I IFNs enhance B cell responses to a soluble Ag as well as to influenza viral infection (17, 30). Here we provided the first evidence that type I IFNs also promote protective B cell response to adenoviral infection. Taken together, these observations demonstrate the importance of innate cytokines such as type I IFNs that are induced immediately after viral infection in the regulation of subsequent adaptive B cell response to pathogens.

The mechanisms underlying type I IFN-dependent enhancement of B cell response remain largely undefined. In addition to the requirement for type I IFNs in early B cell activation as reported (30), we showed that type I IFNs promote differentiation of activated B cells into germinal center cells, which may explain why Ig isotype switching is dependent on type I IFNs as Ig class switching occurs in the germinal centers (17). More importantly, we have demonstrated that induction of Blimp-1 and concomitant suppression of Bcl-6, which allows differentiation of germinal center B cells into Ab-producing plasma cells, are critically dependent on type I IFN signaling. It is not clear whether type I IFNs regulate Blimp-1 and Bcl-6 directly or indirectly through other factors. Thus, it will be important to delineate this process in future studies.

Type I IFN signaling directly on B cells or indirectly on DCs have been accounted for the effect of type I IFNs on enhancement of B cell responses (17, 30, 31). However, the relative contribution of type I IFN signaling on DCs vs on B cells to B cell response remains unknown. Here we provided evidence that while type I IFN signaling on DCs promotes adenovirus-specific IgM, Ig isotype switching and formation of protective neutralizing Ab are critically dependent on type I IFN signaling on B cells. It remains to be defined with regard to the mechanisms responsible for the differential roles of type I IFN signaling on different cell types.

In addition to the direct effect on B cells, indirect signaling on CD4 T cells by type I IFNs is also required for efficient production of protective neutralizing Ab and Ig isotype switching. As B cell response to adenovirus is Th-dependent (31), this result would suggest that type I IFN signaling on CD4 T cells may also be important for activation of Th cells. Indeed, a recent report indicated that direct action of type I IFNs on CD4 T cells is critical for sustaining clonal expansion of activated T cells during a viral infection (32).

In conclusion, we have shown that innate cytokines, type I IFNs induced upon adenoviral infection play a critical role in multiple stages of adaptive B cell response to adenovirus in vivo. We have also demonstrated that although type I IFN signaling on DCs is important for enhancing the production of virus-specific IgM, optimal generation of protective neutralizing Ab relies on type I IFN signaling on both CD4 T and B cells. There results may suggest potential strategies for improving adenovirus-mediated gene therapy in vivo and/or the design of effective vaccines for cancer and infectious diseases.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants CA111807 and CA047741 (to Y.Y.), and an Alliance for Cancer Gene Therapy Grant (to Y.Y.).

² Address correspondence and reprint requests to Dr. Yiping Yang, Departments of Medicine and Immunology, Duke University Medical Center, Box 3502, Durham, NC 27710. E-mail address: yang0029{at}mc.duke.edu

³ Abbreviations used in this paper: DC, dendritic cell; WT, wild type; PNA, peanut agglutinin.

Received for publication October 25, 2006. Accepted for publication January 9, 2007.

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Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 

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