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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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DC–T cell interactions in airway mucosa. (A–C) Confocal microscopy of tracheal sections 2 h after challenge of OVA-immune rats stained for MHC II (green, DCs) and TcRαβ (red, T cells). Dual staining contact points appear yellow. Each panel in the series represents a 1-μm optical section shown in ascending order, where individual DCs can be seen interacting with ≥1 T cells. (D) Individual T cells (n = 50–100) were scored for direct contact with DCs, and numbers in contact were expressed as a percentage of total T cells. Relative numbers of T cells at each time point were determined by factoring in data on absolute cell numbers per unit area of tissue from Fig. 1 D. *, P < 0.05 relative to 0 h, based on mean data from five experiments. (E) IL-2R+ T cells were initially enumerated as a percentage of total T cells by flow cytometric analysis of tracheal digests from exposed (solid bars) or control (open bars) animals in five experiments, and finally expressed as numbers of IL-2R+ T cells per unit area of epithelium by reference to data in Fig. 1 D, yielding five data points for each group at each time point. Data analysis used means derived from these data points. 24 h > 2 h in OVA-exposed animals: *, P < 0.05. (F) Tracheal DCs from naive animals were cultured alone or in the presence of either control or OVA-immune T cells at a density of 20:1 (T cell/DC). After the addition of 50 μg/ml soluble OVA, CD86 expression was examined (as in Fig. 3) at 0 and 3 or 4 h (data shown are for 3 h and are representative of a series of five experiments). Test culture (solid bar) > controls (open bars). *, P < 0.02 based on comparisons of means derived from five data points for each manipulation. Raw data from an exemplary experiment are illustrated in Fig. S9, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1.
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fig5: DC–T cell interactions in airway mucosa. (A–C) Confocal microscopy of tracheal sections 2 h after challenge of OVA-immune rats stained for MHC II (green, DCs) and TcRαβ (red, T cells). Dual staining contact points appear yellow. Each panel in the series represents a 1-μm optical section shown in ascending order, where individual DCs can be seen interacting with ≥1 T cells. (D) Individual T cells (n = 50–100) were scored for direct contact with DCs, and numbers in contact were expressed as a percentage of total T cells. Relative numbers of T cells at each time point were determined by factoring in data on absolute cell numbers per unit area of tissue from Fig. 1 D. *, P < 0.05 relative to 0 h, based on mean data from five experiments. (E) IL-2R+ T cells were initially enumerated as a percentage of total T cells by flow cytometric analysis of tracheal digests from exposed (solid bars) or control (open bars) animals in five experiments, and finally expressed as numbers of IL-2R+ T cells per unit area of epithelium by reference to data in Fig. 1 D, yielding five data points for each group at each time point. Data analysis used means derived from these data points. 24 h > 2 h in OVA-exposed animals: *, P < 0.05. (F) Tracheal DCs from naive animals were cultured alone or in the presence of either control or OVA-immune T cells at a density of 20:1 (T cell/DC). After the addition of 50 μg/ml soluble OVA, CD86 expression was examined (as in Fig. 3) at 0 and 3 or 4 h (data shown are for 3 h and are representative of a series of five experiments). Test culture (solid bar) > controls (open bars). *, P < 0.02 based on comparisons of means derived from five data points for each manipulation. Raw data from an exemplary experiment are illustrated in Fig. S9, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1.

Mentions: Next, we sought to further elucidate the mechanisms underlying T cell–induced DC maturation. The upper panels of Fig. 5 A show DC–T cell interactions in situ in the airway mucosa from an OVA-challenged rat, using confocal microscopy. Fig. 5, A–C, displays optical sections one micron apart, illustrating clustering between DCs (green) and T cells (red; contact regions are yellow). In Fig. 5 D, we scored individual T cells in randomly selected sections at each time point for contact with DCs, clearly demonstrating the continuous high level of interaction between resident DCs and transiting T cells in the resting state, which increases further after challenge. The relative number of clustered T cells was also determined by factoring in information (refer to Fig. 1) on the total number of T cells present at each time point, and it is evident that a progressive increase occurs over the 24 h after allergen challenge. We obtained comparable findings for clustering of CD2+ T cells with DCs (Fig. S8, available at http://www.jem.org/cgi/content/full/jem.20021328/DC1). We sought evidence that these DC–T cell interactions were associated with T cell activation. Analyses of IL-2R expression on isolated airway T cells from challenged animals indicated a marked increase at 24 h (Fig. 5 E). Next, we examined the potential mechanism of CD86 up-regulation by coculture of resting airway DCs with CD4+ T cells from naive or OVA-primed animals, plus soluble OVA, for 3 h, corresponding to 1 h of aerosol exposure plus 2 h of rest before sampling, as used above (Fig. 5 F). The results indicate that CD86 up-regulation required the presence of antigen-specific T memory cells plus antigen. We additionally observed up-regulation of MHC class II expression on these DCs (Fig. S9, available at http://www.jem.org/cgi/content/full/jem.20021328/DC1).


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)

DC–T cell interactions in airway mucosa. (A–C) Confocal microscopy of tracheal sections 2 h after challenge of OVA-immune rats stained for MHC II (green, DCs) and TcRαβ (red, T cells). Dual staining contact points appear yellow. Each panel in the series represents a 1-μm optical section shown in ascending order, where individual DCs can be seen interacting with ≥1 T cells. (D) Individual T cells (n = 50–100) were scored for direct contact with DCs, and numbers in contact were expressed as a percentage of total T cells. Relative numbers of T cells at each time point were determined by factoring in data on absolute cell numbers per unit area of tissue from Fig. 1 D. *, P < 0.05 relative to 0 h, based on mean data from five experiments. (E) IL-2R+ T cells were initially enumerated as a percentage of total T cells by flow cytometric analysis of tracheal digests from exposed (solid bars) or control (open bars) animals in five experiments, and finally expressed as numbers of IL-2R+ T cells per unit area of epithelium by reference to data in Fig. 1 D, yielding five data points for each group at each time point. Data analysis used means derived from these data points. 24 h > 2 h in OVA-exposed animals: *, P < 0.05. (F) Tracheal DCs from naive animals were cultured alone or in the presence of either control or OVA-immune T cells at a density of 20:1 (T cell/DC). After the addition of 50 μg/ml soluble OVA, CD86 expression was examined (as in Fig. 3) at 0 and 3 or 4 h (data shown are for 3 h and are representative of a series of five experiments). Test culture (solid bar) > controls (open bars). *, P < 0.02 based on comparisons of means derived from five data points for each manipulation. Raw data from an exemplary experiment are illustrated in Fig. S9, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1.
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fig5: DC–T cell interactions in airway mucosa. (A–C) Confocal microscopy of tracheal sections 2 h after challenge of OVA-immune rats stained for MHC II (green, DCs) and TcRαβ (red, T cells). Dual staining contact points appear yellow. Each panel in the series represents a 1-μm optical section shown in ascending order, where individual DCs can be seen interacting with ≥1 T cells. (D) Individual T cells (n = 50–100) were scored for direct contact with DCs, and numbers in contact were expressed as a percentage of total T cells. Relative numbers of T cells at each time point were determined by factoring in data on absolute cell numbers per unit area of tissue from Fig. 1 D. *, P < 0.05 relative to 0 h, based on mean data from five experiments. (E) IL-2R+ T cells were initially enumerated as a percentage of total T cells by flow cytometric analysis of tracheal digests from exposed (solid bars) or control (open bars) animals in five experiments, and finally expressed as numbers of IL-2R+ T cells per unit area of epithelium by reference to data in Fig. 1 D, yielding five data points for each group at each time point. Data analysis used means derived from these data points. 24 h > 2 h in OVA-exposed animals: *, P < 0.05. (F) Tracheal DCs from naive animals were cultured alone or in the presence of either control or OVA-immune T cells at a density of 20:1 (T cell/DC). After the addition of 50 μg/ml soluble OVA, CD86 expression was examined (as in Fig. 3) at 0 and 3 or 4 h (data shown are for 3 h and are representative of a series of five experiments). Test culture (solid bar) > controls (open bars). *, P < 0.02 based on comparisons of means derived from five data points for each manipulation. Raw data from an exemplary experiment are illustrated in Fig. S9, available at http://www.jem.org/cgi/content/full.jem.20021328/DC1.
Mentions: Next, we sought to further elucidate the mechanisms underlying T cell–induced DC maturation. The upper panels of Fig. 5 A show DC–T cell interactions in situ in the airway mucosa from an OVA-challenged rat, using confocal microscopy. Fig. 5, A–C, displays optical sections one micron apart, illustrating clustering between DCs (green) and T cells (red; contact regions are yellow). In Fig. 5 D, we scored individual T cells in randomly selected sections at each time point for contact with DCs, clearly demonstrating the continuous high level of interaction between resident DCs and transiting T cells in the resting state, which increases further after challenge. The relative number of clustered T cells was also determined by factoring in information (refer to Fig. 1) on the total number of T cells present at each time point, and it is evident that a progressive increase occurs over the 24 h after allergen challenge. We obtained comparable findings for clustering of CD2+ T cells with DCs (Fig. S8, available at http://www.jem.org/cgi/content/full/jem.20021328/DC1). We sought evidence that these DC–T cell interactions were associated with T cell activation. Analyses of IL-2R expression on isolated airway T cells from challenged animals indicated a marked increase at 24 h (Fig. 5 E). Next, we examined the potential mechanism of CD86 up-regulation by coculture of resting airway DCs with CD4+ T cells from naive or OVA-primed animals, plus soluble OVA, for 3 h, corresponding to 1 h of aerosol exposure plus 2 h of rest before sampling, as used above (Fig. 5 F). The results indicate that CD86 up-regulation required the presence of antigen-specific T memory cells plus antigen. We additionally observed up-regulation of MHC class II expression on these DCs (Fig. S9, available at http://www.jem.org/cgi/content/full/jem.20021328/DC1).

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