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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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Coadministration of OVA and influenza virus leads to formation of OVA specific cytokine producing effector cells. B6 mice were injected with 106 OT-I or OT-II T cells intravenously on day 0. Day 1 mice were infected with X-31 or mock infected and administered egg OVA on day 2, 3, and 4. On day 6 the draining lymph nodes were harvested and 5 × 106 cells were cultured for 5 h with SIINFEKL (OT-I) or OVA323–339 (OT-II) in the presence of Brefeldin A. After harvesting, the cells were stained for expression of CD45.1 and CD4/CD8 and intracellular IL-2 or IFN-γ. The response of OT-II T cells (A) and OT-I T cells (B) is shown for cell numbers (top rows) and IFN-γ/IL-2 production (middle and lower rows) in the mediastinal LNs. Data are representative of two experiments.
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fig3: Coadministration of OVA and influenza virus leads to formation of OVA specific cytokine producing effector cells. B6 mice were injected with 106 OT-I or OT-II T cells intravenously on day 0. Day 1 mice were infected with X-31 or mock infected and administered egg OVA on day 2, 3, and 4. On day 6 the draining lymph nodes were harvested and 5 × 106 cells were cultured for 5 h with SIINFEKL (OT-I) or OVA323–339 (OT-II) in the presence of Brefeldin A. After harvesting, the cells were stained for expression of CD45.1 and CD4/CD8 and intracellular IL-2 or IFN-γ. The response of OT-II T cells (A) and OT-I T cells (B) is shown for cell numbers (top rows) and IFN-γ/IL-2 production (middle and lower rows) in the mediastinal LNs. Data are representative of two experiments.

Mentions: As we observed comparable proliferation of OT-I and OT-II T cells in mice given aerosol OVA without or with influenza virus (Fig. 2), we were interested in determining the differentiation of these T cells into effector cells in vivo. Mice were given the transgenic T cells at day 0, influenza or mock infected at day 1, and then given 3 doses of egg OVA on days 2, 3, and 4. On day 6, the lymph node cells were isolated, and stimulated 5 h with OVA peptides appropriate for the antigen presenting H-2Kb and I-Ab molecules. T cells were then studied by flow cytometry to monitor T cell numbers as well as the intracellular accumulation of IL-2 and IFN-γ. Administration of egg OVA, with or without influenza virus infection, expanded the numbers of T cells as expected from the prior CFSE experiments (Fig. 2), although the expansion in T cell numbers at day 6 was threefold higher if there was influenza coinfection (Fig. 3, A and B, top rows). More dramatic differences were noted at the level of cytokine production, as much higher proportions of OT-I and OT-II T cells producing IL-2 and IFN-γ were detected when mice were aerosolized with influenza virus and egg OVA, and virtually no cytokine production was seen in the absence of influenza virus (Fig. 3, A and B, middle and lower rows). OVA-specific, transgenic T cells from mice treated only with influenza virus or PBS did not produce significant cytokines, i.e., little IL-2 or IFN-γ was detected (Fig. 3) and no IL-4 or IL-10 (unpublished data). Therefore influenza virus infection has a striking effect on the functional outcome of the OVA specific T cell response, leading to IL-2 and IFN-γ production.


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)

Coadministration of OVA and influenza virus leads to formation of OVA specific cytokine producing effector cells. B6 mice were injected with 106 OT-I or OT-II T cells intravenously on day 0. Day 1 mice were infected with X-31 or mock infected and administered egg OVA on day 2, 3, and 4. On day 6 the draining lymph nodes were harvested and 5 × 106 cells were cultured for 5 h with SIINFEKL (OT-I) or OVA323–339 (OT-II) in the presence of Brefeldin A. After harvesting, the cells were stained for expression of CD45.1 and CD4/CD8 and intracellular IL-2 or IFN-γ. The response of OT-II T cells (A) and OT-I T cells (B) is shown for cell numbers (top rows) and IFN-γ/IL-2 production (middle and lower rows) in the mediastinal LNs. Data are representative of two experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196079&req=5

fig3: Coadministration of OVA and influenza virus leads to formation of OVA specific cytokine producing effector cells. B6 mice were injected with 106 OT-I or OT-II T cells intravenously on day 0. Day 1 mice were infected with X-31 or mock infected and administered egg OVA on day 2, 3, and 4. On day 6 the draining lymph nodes were harvested and 5 × 106 cells were cultured for 5 h with SIINFEKL (OT-I) or OVA323–339 (OT-II) in the presence of Brefeldin A. After harvesting, the cells were stained for expression of CD45.1 and CD4/CD8 and intracellular IL-2 or IFN-γ. The response of OT-II T cells (A) and OT-I T cells (B) is shown for cell numbers (top rows) and IFN-γ/IL-2 production (middle and lower rows) in the mediastinal LNs. Data are representative of two experiments.
Mentions: As we observed comparable proliferation of OT-I and OT-II T cells in mice given aerosol OVA without or with influenza virus (Fig. 2), we were interested in determining the differentiation of these T cells into effector cells in vivo. Mice were given the transgenic T cells at day 0, influenza or mock infected at day 1, and then given 3 doses of egg OVA on days 2, 3, and 4. On day 6, the lymph node cells were isolated, and stimulated 5 h with OVA peptides appropriate for the antigen presenting H-2Kb and I-Ab molecules. T cells were then studied by flow cytometry to monitor T cell numbers as well as the intracellular accumulation of IL-2 and IFN-γ. Administration of egg OVA, with or without influenza virus infection, expanded the numbers of T cells as expected from the prior CFSE experiments (Fig. 2), although the expansion in T cell numbers at day 6 was threefold higher if there was influenza coinfection (Fig. 3, A and B, top rows). More dramatic differences were noted at the level of cytokine production, as much higher proportions of OT-I and OT-II T cells producing IL-2 and IFN-γ were detected when mice were aerosolized with influenza virus and egg OVA, and virtually no cytokine production was seen in the absence of influenza virus (Fig. 3, A and B, middle and lower rows). OVA-specific, transgenic T cells from mice treated only with influenza virus or PBS did not produce significant cytokines, i.e., little IL-2 or IFN-γ was detected (Fig. 3) and no IL-4 or IL-10 (unpublished data). Therefore influenza virus infection has a striking effect on the functional outcome of the OVA specific T cell response, leading to IL-2 and IFN-γ production.

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