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Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma.

Huh JC, Strickland DH, Jahnsen FL, Turner DJ, Thomas JA, Napoli S, Tobagus I, Stumbles PA, Sly PD, Holt PG - J. Exp. Med. (2003)

Bottom Line: Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway.Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen.The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators.

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western, Australia 6008.

ABSTRACT
The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.

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Flow cytometric analysis of DCs after OVA aerosol challenge of OVA-primed animals. Data are representative of a series (A, E, and F) or mean ± SE from three to five experiments. (A) Flow cytometric analysis of total tracheal digest cells indicating gating for total DCs (R1) and subregions (R2–R4), based on SSC and MHC class II expression profiles. (B) Surface marker expression (after correction for background staining with isotype control) in total MHC class II+ DC populations (R1) in the trachea at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge (*, P < 0.01 compared with 0 and 24 h). (C) Endocytic activity of R1 tracheal DCs at 2, 24, and 48 h after challenge as determined by 10-min dextran FITC uptake with trypan blue quenching at 37°C minus uptake at 4°C. Activity was significantly reduced relative to unexposed animals (0 h). *, P < 0.04; **, P < 0.01. (D) Relative numeric changes in tracheal DCs within each gating region at 2 (solid bars) and 24 h (hatched bars) after challenge compared with control immunized, nonaerosol challenged animals (open bars). (E and F) Expression of CD86 and MHC class II by R4 tracheal DCs at 2 h after challenge. Nonspecific binding of isotype control (E) versus staining with anti-CD86 on the MHC class IIhi subset. (G) Changes in CD86 expression on tracheal DCs in subregions R2–R4 as designated in A and D. Significance of increase relative to 0 h. *, P < 0.01; **, P < 0.001. (H) Flow cytometry analysis of DCs in PTLN after aerosol challenge of sensitized animals. The gating strategy comprised initial selection of total DCs (as per R1 in A), followed sequentially by gating for high MHC class II and low isotype control binding, and the same gates applied directly to obtain percentage of CD86 expression (see Fig. S5, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1). MHC class IIhi CD86hi DCs are shown as percentage of total DCs at 0 h compared with animals at 2, 24, and 48 h after challenge. >0 h: *, P < 0.01; **, P < 0.001. (J) Surface marker expressions by R1 DCs in the parenchymal lung at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge. (K) Endocytic activity of R1 parenchymal lung DCs at 24 h after challenge compared to unexposed animals (t0), determined as per C.
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fig3: Flow cytometric analysis of DCs after OVA aerosol challenge of OVA-primed animals. Data are representative of a series (A, E, and F) or mean ± SE from three to five experiments. (A) Flow cytometric analysis of total tracheal digest cells indicating gating for total DCs (R1) and subregions (R2–R4), based on SSC and MHC class II expression profiles. (B) Surface marker expression (after correction for background staining with isotype control) in total MHC class II+ DC populations (R1) in the trachea at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge (*, P < 0.01 compared with 0 and 24 h). (C) Endocytic activity of R1 tracheal DCs at 2, 24, and 48 h after challenge as determined by 10-min dextran FITC uptake with trypan blue quenching at 37°C minus uptake at 4°C. Activity was significantly reduced relative to unexposed animals (0 h). *, P < 0.04; **, P < 0.01. (D) Relative numeric changes in tracheal DCs within each gating region at 2 (solid bars) and 24 h (hatched bars) after challenge compared with control immunized, nonaerosol challenged animals (open bars). (E and F) Expression of CD86 and MHC class II by R4 tracheal DCs at 2 h after challenge. Nonspecific binding of isotype control (E) versus staining with anti-CD86 on the MHC class IIhi subset. (G) Changes in CD86 expression on tracheal DCs in subregions R2–R4 as designated in A and D. Significance of increase relative to 0 h. *, P < 0.01; **, P < 0.001. (H) Flow cytometry analysis of DCs in PTLN after aerosol challenge of sensitized animals. The gating strategy comprised initial selection of total DCs (as per R1 in A), followed sequentially by gating for high MHC class II and low isotype control binding, and the same gates applied directly to obtain percentage of CD86 expression (see Fig. S5, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1). MHC class IIhi CD86hi DCs are shown as percentage of total DCs at 0 h compared with animals at 2, 24, and 48 h after challenge. >0 h: *, P < 0.01; **, P < 0.001. (J) Surface marker expressions by R1 DCs in the parenchymal lung at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge. (K) Endocytic activity of R1 parenchymal lung DCs at 24 h after challenge compared to unexposed animals (t0), determined as per C.

Mentions: AHR after exposure to aerosolized OVA. Sensitized animals (n = 6 per group; ○) together with naive controls (•) were exposed to aerosolized OVA, and 24 h later MCh challenge was performed. The top shows a left shift in the airway dose response curve to MCh contrasted with no change in parenchymal responsiveness (bottom). Differences between test and control groups in this experiment (and in Figs. 3–6) were analyzed by Student's t test. *, P < 0.01; **, P < 0.05.


Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma.

Huh JC, Strickland DH, Jahnsen FL, Turner DJ, Thomas JA, Napoli S, Tobagus I, Stumbles PA, Sly PD, Holt PG - J. Exp. Med. (2003)

Flow cytometric analysis of DCs after OVA aerosol challenge of OVA-primed animals. Data are representative of a series (A, E, and F) or mean ± SE from three to five experiments. (A) Flow cytometric analysis of total tracheal digest cells indicating gating for total DCs (R1) and subregions (R2–R4), based on SSC and MHC class II expression profiles. (B) Surface marker expression (after correction for background staining with isotype control) in total MHC class II+ DC populations (R1) in the trachea at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge (*, P < 0.01 compared with 0 and 24 h). (C) Endocytic activity of R1 tracheal DCs at 2, 24, and 48 h after challenge as determined by 10-min dextran FITC uptake with trypan blue quenching at 37°C minus uptake at 4°C. Activity was significantly reduced relative to unexposed animals (0 h). *, P < 0.04; **, P < 0.01. (D) Relative numeric changes in tracheal DCs within each gating region at 2 (solid bars) and 24 h (hatched bars) after challenge compared with control immunized, nonaerosol challenged animals (open bars). (E and F) Expression of CD86 and MHC class II by R4 tracheal DCs at 2 h after challenge. Nonspecific binding of isotype control (E) versus staining with anti-CD86 on the MHC class IIhi subset. (G) Changes in CD86 expression on tracheal DCs in subregions R2–R4 as designated in A and D. Significance of increase relative to 0 h. *, P < 0.01; **, P < 0.001. (H) Flow cytometry analysis of DCs in PTLN after aerosol challenge of sensitized animals. The gating strategy comprised initial selection of total DCs (as per R1 in A), followed sequentially by gating for high MHC class II and low isotype control binding, and the same gates applied directly to obtain percentage of CD86 expression (see Fig. S5, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1). MHC class IIhi CD86hi DCs are shown as percentage of total DCs at 0 h compared with animals at 2, 24, and 48 h after challenge. >0 h: *, P < 0.01; **, P < 0.001. (J) Surface marker expressions by R1 DCs in the parenchymal lung at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge. (K) Endocytic activity of R1 parenchymal lung DCs at 24 h after challenge compared to unexposed animals (t0), determined as per C.
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Related In: Results  -  Collection

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fig3: Flow cytometric analysis of DCs after OVA aerosol challenge of OVA-primed animals. Data are representative of a series (A, E, and F) or mean ± SE from three to five experiments. (A) Flow cytometric analysis of total tracheal digest cells indicating gating for total DCs (R1) and subregions (R2–R4), based on SSC and MHC class II expression profiles. (B) Surface marker expression (after correction for background staining with isotype control) in total MHC class II+ DC populations (R1) in the trachea at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge (*, P < 0.01 compared with 0 and 24 h). (C) Endocytic activity of R1 tracheal DCs at 2, 24, and 48 h after challenge as determined by 10-min dextran FITC uptake with trypan blue quenching at 37°C minus uptake at 4°C. Activity was significantly reduced relative to unexposed animals (0 h). *, P < 0.04; **, P < 0.01. (D) Relative numeric changes in tracheal DCs within each gating region at 2 (solid bars) and 24 h (hatched bars) after challenge compared with control immunized, nonaerosol challenged animals (open bars). (E and F) Expression of CD86 and MHC class II by R4 tracheal DCs at 2 h after challenge. Nonspecific binding of isotype control (E) versus staining with anti-CD86 on the MHC class IIhi subset. (G) Changes in CD86 expression on tracheal DCs in subregions R2–R4 as designated in A and D. Significance of increase relative to 0 h. *, P < 0.01; **, P < 0.001. (H) Flow cytometry analysis of DCs in PTLN after aerosol challenge of sensitized animals. The gating strategy comprised initial selection of total DCs (as per R1 in A), followed sequentially by gating for high MHC class II and low isotype control binding, and the same gates applied directly to obtain percentage of CD86 expression (see Fig. S5, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1). MHC class IIhi CD86hi DCs are shown as percentage of total DCs at 0 h compared with animals at 2, 24, and 48 h after challenge. >0 h: *, P < 0.01; **, P < 0.001. (J) Surface marker expressions by R1 DCs in the parenchymal lung at 0 (open bars), 2 (solid bars), and 24 h (hatched bars) after challenge. (K) Endocytic activity of R1 parenchymal lung DCs at 24 h after challenge compared to unexposed animals (t0), determined as per C.
Mentions: AHR after exposure to aerosolized OVA. Sensitized animals (n = 6 per group; ○) together with naive controls (•) were exposed to aerosolized OVA, and 24 h later MCh challenge was performed. The top shows a left shift in the airway dose response curve to MCh contrasted with no change in parenchymal responsiveness (bottom). Differences between test and control groups in this experiment (and in Figs. 3–6) were analyzed by Student's t test. *, P < 0.01; **, P < 0.05.

Bottom Line: Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway.Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen.The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators.

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, Faculty of Medicine and Dentistry, The University of Western Australia, Perth, Western, Australia 6008.

ABSTRACT
The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.

Show MeSH
Related in: MedlinePlus