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Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein.

Brimnes MK, Bonifaz L, Steinman RM, Moran TM - J. Exp. Med. (2003)

Bottom Line: In its absence, OVA failed to induce B and T cell responses and even tolerized, but with influenza, OVA-specific antibodies and CD8+ cytolytic T lymphocytes developed.The relatively slow (2-3 d) kinetics of maturation correlated closely to the time at which OVA inhalation elicited specific antibodies.Therefore respiratory infection can induce DC maturation and simultaneously B and T cell immunity to an innocuous antigen inhaled concurrently.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, 10029 NY, USA.

ABSTRACT
We evaluated the proposal that during microbial infection, dendritic cells (DCs) undergo maturation and present a mixture of peptides derived from the microbe as well as harmless environmental antigens. Mice were exposed to an aerosol of endotoxin free ovalbumin (OVA) in the absence or presence of influenza virus. In its absence, OVA failed to induce B and T cell responses and even tolerized, but with influenza, OVA-specific antibodies and CD8+ cytolytic T lymphocytes developed. With or without infection, OVA was presented selectively in the draining mediastinal lymph nodes, as assessed by the comparable proliferation of infused, CD8+ and CD4+, TCR transgenic T cells. In the absence of influenza, these OVA-specific T cells produced little IL-2, IL-4, IL-10, and IFN-gamma, but with infection, both CD4+ and CD8+ T cells made high levels of IL-2 and IFN-gamma. The OVA plus influenza-treated mice also showed accelerated recovery to a challenge with recombinant vaccinia OVA virus. CD11c+ DCs from the mediastinal lymph nodes of infected mice selectively stimulated both OVA- and influenza-specific T cells and underwent maturation, with higher levels of MHC class II, CD80, and CD86 molecules. The relatively slow (2-3 d) kinetics of maturation correlated closely to the time at which OVA inhalation elicited specific antibodies. Therefore respiratory infection can induce DC maturation and simultaneously B and T cell immunity to an innocuous antigen inhaled concurrently.

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Generation of protective immunity following coadministration of OVA and influenza virus. B6 mice were infected with aerosolized X-31 on day 1 and administered egg OVA on day 2, 3, and 4. 3 wk after infection the groups that received X-31 (influenza + egg OVA and influenza) were infected with B/Lee and boosted with egg OVA for three consecutive days (only influenza + egg OVA and egg OVA groups). 3 wk after infection with B/Lee all the groups were challenged with 105 pfu/mouse Vaccinia-OVA intranasally. 7 d after vaccinia-OVA infection the lungs were harvested and analyzed for virus and the spleen was assayed for IFN-γ–producing T cells. Also, the serum was collected after each administration of egg OVA to measure production of OVA specific antibodies. (A) Vaccinia virus titer in lungs. Data are expressed as mean ± SD from groups of five mice. The difference between the influenza + egg OVA and the influenza group was statistically significant (*P < 0.05). Data are representative of four independent experiments. (B) Weight loss in mice infected with vaccinia–OVA. (C) Production of IFN-γ from CD8 T cells from spleen cells restimulated with SIINFEKL. Data are representative of two independent experiments. (D) OVA specific IgG1 antibody production after primary immunization (influenza A + egg OVA), secondary immunization (influenza B + egg OVA), and tertiary immunization (vaccinia-OVA). Antibodies (IgG1 and IgG2b [unpublished data]) were observed only in the serum of animals given OVA and virus infection. The results shown are 1:100 serum dilutions but identical results were observed with a 1:10 dilution. Data are expressed as mean ± SD from groups of five mice.
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fig7: Generation of protective immunity following coadministration of OVA and influenza virus. B6 mice were infected with aerosolized X-31 on day 1 and administered egg OVA on day 2, 3, and 4. 3 wk after infection the groups that received X-31 (influenza + egg OVA and influenza) were infected with B/Lee and boosted with egg OVA for three consecutive days (only influenza + egg OVA and egg OVA groups). 3 wk after infection with B/Lee all the groups were challenged with 105 pfu/mouse Vaccinia-OVA intranasally. 7 d after vaccinia-OVA infection the lungs were harvested and analyzed for virus and the spleen was assayed for IFN-γ–producing T cells. Also, the serum was collected after each administration of egg OVA to measure production of OVA specific antibodies. (A) Vaccinia virus titer in lungs. Data are expressed as mean ± SD from groups of five mice. The difference between the influenza + egg OVA and the influenza group was statistically significant (*P < 0.05). Data are representative of four independent experiments. (B) Weight loss in mice infected with vaccinia–OVA. (C) Production of IFN-γ from CD8 T cells from spleen cells restimulated with SIINFEKL. Data are representative of two independent experiments. (D) OVA specific IgG1 antibody production after primary immunization (influenza A + egg OVA), secondary immunization (influenza B + egg OVA), and tertiary immunization (vaccinia-OVA). Antibodies (IgG1 and IgG2b [unpublished data]) were observed only in the serum of animals given OVA and virus infection. The results shown are 1:100 serum dilutions but identical results were observed with a 1:10 dilution. Data are expressed as mean ± SD from groups of five mice.

Mentions: As shown in Fig. 7 A, mice treated with both influenza and egg OVA had a significantly lower vaccinia virus titer compared with all the control groups. The influenza group, the most important control group, had 7 times higher vaccinia titers than influenza egg OVA groups, while the two other control groups had 40–60 times higher virus titers. Losses of body weight, as a manifestation of influenza infection, were also monitored (Fig. 7 B). The weight loss data correlated with the virus titers in the lungs, i.e., there was much less weight loss in protected animals with lower virus titers. We also assayed the production of IFN-γ from CD8+ T cells in the spleens of OVA-vaccinia challenged mice and found that mice administered egg OVA in the presence of influenza virus had a higher proportion of IFN-γ producing CD8+ T cells when restimulated with the OT-I peptide (SIINFEKL) relative to the other experimental groups (Fig. 7 C). In the same mice we analyzed the OVA specific antibody response after administration of egg OVA to follow the priming of the mice. As shown in Fig. 7 D, the level of OVA-specific antibodies increased from the first immunization to the second OVA exposure, and after challenge with vaccinia–OVA, antibody levels were further enhanced. Importantly, there was no demonstrable OVA-specific antibodies in mice administered egg OVA only, even after exposure to OVA seven times over a 7-wk period. These mice failed to make any detectable level of antibody, emphasizing that endotoxin free OVA is not immunogenic via the airway but induces protective OVA-specific immunity if inhaled during an influenza infection.


Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein.

Brimnes MK, Bonifaz L, Steinman RM, Moran TM - J. Exp. Med. (2003)

Generation of protective immunity following coadministration of OVA and influenza virus. B6 mice were infected with aerosolized X-31 on day 1 and administered egg OVA on day 2, 3, and 4. 3 wk after infection the groups that received X-31 (influenza + egg OVA and influenza) were infected with B/Lee and boosted with egg OVA for three consecutive days (only influenza + egg OVA and egg OVA groups). 3 wk after infection with B/Lee all the groups were challenged with 105 pfu/mouse Vaccinia-OVA intranasally. 7 d after vaccinia-OVA infection the lungs were harvested and analyzed for virus and the spleen was assayed for IFN-γ–producing T cells. Also, the serum was collected after each administration of egg OVA to measure production of OVA specific antibodies. (A) Vaccinia virus titer in lungs. Data are expressed as mean ± SD from groups of five mice. The difference between the influenza + egg OVA and the influenza group was statistically significant (*P < 0.05). Data are representative of four independent experiments. (B) Weight loss in mice infected with vaccinia–OVA. (C) Production of IFN-γ from CD8 T cells from spleen cells restimulated with SIINFEKL. Data are representative of two independent experiments. (D) OVA specific IgG1 antibody production after primary immunization (influenza A + egg OVA), secondary immunization (influenza B + egg OVA), and tertiary immunization (vaccinia-OVA). Antibodies (IgG1 and IgG2b [unpublished data]) were observed only in the serum of animals given OVA and virus infection. The results shown are 1:100 serum dilutions but identical results were observed with a 1:10 dilution. Data are expressed as mean ± SD from groups of five mice.
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Related In: Results  -  Collection

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fig7: Generation of protective immunity following coadministration of OVA and influenza virus. B6 mice were infected with aerosolized X-31 on day 1 and administered egg OVA on day 2, 3, and 4. 3 wk after infection the groups that received X-31 (influenza + egg OVA and influenza) were infected with B/Lee and boosted with egg OVA for three consecutive days (only influenza + egg OVA and egg OVA groups). 3 wk after infection with B/Lee all the groups were challenged with 105 pfu/mouse Vaccinia-OVA intranasally. 7 d after vaccinia-OVA infection the lungs were harvested and analyzed for virus and the spleen was assayed for IFN-γ–producing T cells. Also, the serum was collected after each administration of egg OVA to measure production of OVA specific antibodies. (A) Vaccinia virus titer in lungs. Data are expressed as mean ± SD from groups of five mice. The difference between the influenza + egg OVA and the influenza group was statistically significant (*P < 0.05). Data are representative of four independent experiments. (B) Weight loss in mice infected with vaccinia–OVA. (C) Production of IFN-γ from CD8 T cells from spleen cells restimulated with SIINFEKL. Data are representative of two independent experiments. (D) OVA specific IgG1 antibody production after primary immunization (influenza A + egg OVA), secondary immunization (influenza B + egg OVA), and tertiary immunization (vaccinia-OVA). Antibodies (IgG1 and IgG2b [unpublished data]) were observed only in the serum of animals given OVA and virus infection. The results shown are 1:100 serum dilutions but identical results were observed with a 1:10 dilution. Data are expressed as mean ± SD from groups of five mice.
Mentions: As shown in Fig. 7 A, mice treated with both influenza and egg OVA had a significantly lower vaccinia virus titer compared with all the control groups. The influenza group, the most important control group, had 7 times higher vaccinia titers than influenza egg OVA groups, while the two other control groups had 40–60 times higher virus titers. Losses of body weight, as a manifestation of influenza infection, were also monitored (Fig. 7 B). The weight loss data correlated with the virus titers in the lungs, i.e., there was much less weight loss in protected animals with lower virus titers. We also assayed the production of IFN-γ from CD8+ T cells in the spleens of OVA-vaccinia challenged mice and found that mice administered egg OVA in the presence of influenza virus had a higher proportion of IFN-γ producing CD8+ T cells when restimulated with the OT-I peptide (SIINFEKL) relative to the other experimental groups (Fig. 7 C). In the same mice we analyzed the OVA specific antibody response after administration of egg OVA to follow the priming of the mice. As shown in Fig. 7 D, the level of OVA-specific antibodies increased from the first immunization to the second OVA exposure, and after challenge with vaccinia–OVA, antibody levels were further enhanced. Importantly, there was no demonstrable OVA-specific antibodies in mice administered egg OVA only, even after exposure to OVA seven times over a 7-wk period. These mice failed to make any detectable level of antibody, emphasizing that endotoxin free OVA is not immunogenic via the airway but induces protective OVA-specific immunity if inhaled during an influenza infection.

Bottom Line: In its absence, OVA failed to induce B and T cell responses and even tolerized, but with influenza, OVA-specific antibodies and CD8+ cytolytic T lymphocytes developed.The relatively slow (2-3 d) kinetics of maturation correlated closely to the time at which OVA inhalation elicited specific antibodies.Therefore respiratory infection can induce DC maturation and simultaneously B and T cell immunity to an innocuous antigen inhaled concurrently.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, 10029 NY, USA.

ABSTRACT
We evaluated the proposal that during microbial infection, dendritic cells (DCs) undergo maturation and present a mixture of peptides derived from the microbe as well as harmless environmental antigens. Mice were exposed to an aerosol of endotoxin free ovalbumin (OVA) in the absence or presence of influenza virus. In its absence, OVA failed to induce B and T cell responses and even tolerized, but with influenza, OVA-specific antibodies and CD8+ cytolytic T lymphocytes developed. With or without infection, OVA was presented selectively in the draining mediastinal lymph nodes, as assessed by the comparable proliferation of infused, CD8+ and CD4+, TCR transgenic T cells. In the absence of influenza, these OVA-specific T cells produced little IL-2, IL-4, IL-10, and IFN-gamma, but with infection, both CD4+ and CD8+ T cells made high levels of IL-2 and IFN-gamma. The OVA plus influenza-treated mice also showed accelerated recovery to a challenge with recombinant vaccinia OVA virus. CD11c+ DCs from the mediastinal lymph nodes of infected mice selectively stimulated both OVA- and influenza-specific T cells and underwent maturation, with higher levels of MHC class II, CD80, and CD86 molecules. The relatively slow (2-3 d) kinetics of maturation correlated closely to the time at which OVA inhalation elicited specific antibodies. Therefore respiratory infection can induce DC maturation and simultaneously B and T cell immunity to an innocuous antigen inhaled concurrently.

Show MeSH
Related in: MedlinePlus