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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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Antigen presentation by purified airway and lymph node DCs. Purified DCs from challenged animals were used to stimulate a CD4+ OVA-specific T cell line for 48 h. T cell stimulation (3H-DNA synthesis as CPM/culture) is shown as mean ± SE from three or more experiments (A and B) or from individual experiments (C). (A) OVA presentation by tracheal DCs isolated from OVA-immune animals 2 (•) and 24 h (▪) after challenge, or from naive animals 2 h (⋄) after challenge. 2 h > 0 h and 24 h: *, P < 0.05–0.01. (B) Total PTLN DCs were purified at 2 (•) or 24 h (□) after OVA aerosol challenge and additionally, sorted into MHC class IIhi (♦) or MHC class IIlow (▵) expressing cells (as per Fig. 3) at the 24-h time point. OVA presentation by PTLN DCs is maximal at 24 h after aerosol challenge and was restricted to the MHC class IIhi population of DCs. (C) Tracheal DCs isolated 2 h after challenge were used to stimulate OVA-specific T cells in the absence (□) or presence (▪) of blocking antibody to CD86. In experiments 3 and 4, control cultures contained isotype control mAb versus medium only in control cultures in experiments 1 and 2. Data are normalized against the OVA-specific T cell response (3H-DNA synthesis at 72 h) in the absence of blocking antibody. <control: *, P < 0.05; **, P < 0.01.
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fig4: Antigen presentation by purified airway and lymph node DCs. Purified DCs from challenged animals were used to stimulate a CD4+ OVA-specific T cell line for 48 h. T cell stimulation (3H-DNA synthesis as CPM/culture) is shown as mean ± SE from three or more experiments (A and B) or from individual experiments (C). (A) OVA presentation by tracheal DCs isolated from OVA-immune animals 2 (•) and 24 h (▪) after challenge, or from naive animals 2 h (⋄) after challenge. 2 h > 0 h and 24 h: *, P < 0.05–0.01. (B) Total PTLN DCs were purified at 2 (•) or 24 h (□) after OVA aerosol challenge and additionally, sorted into MHC class IIhi (♦) or MHC class IIlow (▵) expressing cells (as per Fig. 3) at the 24-h time point. OVA presentation by PTLN DCs is maximal at 24 h after aerosol challenge and was restricted to the MHC class IIhi population of DCs. (C) Tracheal DCs isolated 2 h after challenge were used to stimulate OVA-specific T cells in the absence (□) or presence (▪) of blocking antibody to CD86. In experiments 3 and 4, control cultures contained isotype control mAb versus medium only in control cultures in experiments 1 and 2. Data are normalized against the OVA-specific T cell response (3H-DNA synthesis at 72 h) in the absence of blocking antibody. <control: *, P < 0.05; **, P < 0.01.

Mentions: In Fig. 4 we addressed the central issue of the APC function of these DCs, in particular the presentation of OVA acquired in vivo during aerosol challenge. In these experiments DCs were sorted to >95% purity from tracheas and PTLN of OVA-immune and naive rats before and after OVA aerosol exposure, and cocultured with OVA-responsive CD4+ T cells. The resultant T cell activation was measured as 3H-DNA synthesis. Consistent with previous findings (10), DCs from OVA aerosol–exposed naive rats induced minimal OVA-specific T cell proliferation. However, in OVA-sensitized animals, OVA-bearing DCs expressing mature APC activity were observed in the tracheal mucosa 2 h after OVA exposure (Fig. 4 A). These cells were no longer present in the mucosa at 24 h (Fig. 4 A), but MHC class IIhi DCs with correspondingly high levels of OVA-specific APC activity now appeared de novo in the draining PTLN (Fig. 4 B). Taken together with earlier observations of migration of antigen-bearing DCs to thoracic lymph nodes in rats (12) and mice (18) after airway challenge via intratracheal instillation, and the demonstration above of the sequential appearance of MHC class IIhi CD86hi DCs in the airway mucosa and subsequently the PTLN, these findings are consistent with onward migration of OVA-presenting DCs from the site of antigen deposition in the airway to the draining lymph node. Although it is likely that such migrating DCs might be responsible for the transient peak of OVA-specific APC activity observed in the PTLN (Fig. 4 B), the possibility that airway-derived DCs may pass on antigen to their lymph node counterparts (which in turn become activated) cannot be excluded. In the experiments shown in Fig. 4 C we demonstrate that the in vitro APC activity of the airway DCs sampled at 2 h after OVA exposure can be partially blocked by mAb against the costimulator CD86. The efficiency of this blockade ranged from 25 to 55%.


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)

Antigen presentation by purified airway and lymph node DCs. Purified DCs from challenged animals were used to stimulate a CD4+ OVA-specific T cell line for 48 h. T cell stimulation (3H-DNA synthesis as CPM/culture) is shown as mean ± SE from three or more experiments (A and B) or from individual experiments (C). (A) OVA presentation by tracheal DCs isolated from OVA-immune animals 2 (•) and 24 h (▪) after challenge, or from naive animals 2 h (⋄) after challenge. 2 h > 0 h and 24 h: *, P < 0.05–0.01. (B) Total PTLN DCs were purified at 2 (•) or 24 h (□) after OVA aerosol challenge and additionally, sorted into MHC class IIhi (♦) or MHC class IIlow (▵) expressing cells (as per Fig. 3) at the 24-h time point. OVA presentation by PTLN DCs is maximal at 24 h after aerosol challenge and was restricted to the MHC class IIhi population of DCs. (C) Tracheal DCs isolated 2 h after challenge were used to stimulate OVA-specific T cells in the absence (□) or presence (▪) of blocking antibody to CD86. In experiments 3 and 4, control cultures contained isotype control mAb versus medium only in control cultures in experiments 1 and 2. Data are normalized against the OVA-specific T cell response (3H-DNA synthesis at 72 h) in the absence of blocking antibody. <control: *, P < 0.05; **, P < 0.01.
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Related In: Results  -  Collection

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fig4: Antigen presentation by purified airway and lymph node DCs. Purified DCs from challenged animals were used to stimulate a CD4+ OVA-specific T cell line for 48 h. T cell stimulation (3H-DNA synthesis as CPM/culture) is shown as mean ± SE from three or more experiments (A and B) or from individual experiments (C). (A) OVA presentation by tracheal DCs isolated from OVA-immune animals 2 (•) and 24 h (▪) after challenge, or from naive animals 2 h (⋄) after challenge. 2 h > 0 h and 24 h: *, P < 0.05–0.01. (B) Total PTLN DCs were purified at 2 (•) or 24 h (□) after OVA aerosol challenge and additionally, sorted into MHC class IIhi (♦) or MHC class IIlow (▵) expressing cells (as per Fig. 3) at the 24-h time point. OVA presentation by PTLN DCs is maximal at 24 h after aerosol challenge and was restricted to the MHC class IIhi population of DCs. (C) Tracheal DCs isolated 2 h after challenge were used to stimulate OVA-specific T cells in the absence (□) or presence (▪) of blocking antibody to CD86. In experiments 3 and 4, control cultures contained isotype control mAb versus medium only in control cultures in experiments 1 and 2. Data are normalized against the OVA-specific T cell response (3H-DNA synthesis at 72 h) in the absence of blocking antibody. <control: *, P < 0.05; **, P < 0.01.
Mentions: In Fig. 4 we addressed the central issue of the APC function of these DCs, in particular the presentation of OVA acquired in vivo during aerosol challenge. In these experiments DCs were sorted to >95% purity from tracheas and PTLN of OVA-immune and naive rats before and after OVA aerosol exposure, and cocultured with OVA-responsive CD4+ T cells. The resultant T cell activation was measured as 3H-DNA synthesis. Consistent with previous findings (10), DCs from OVA aerosol–exposed naive rats induced minimal OVA-specific T cell proliferation. However, in OVA-sensitized animals, OVA-bearing DCs expressing mature APC activity were observed in the tracheal mucosa 2 h after OVA exposure (Fig. 4 A). These cells were no longer present in the mucosa at 24 h (Fig. 4 A), but MHC class IIhi DCs with correspondingly high levels of OVA-specific APC activity now appeared de novo in the draining PTLN (Fig. 4 B). Taken together with earlier observations of migration of antigen-bearing DCs to thoracic lymph nodes in rats (12) and mice (18) after airway challenge via intratracheal instillation, and the demonstration above of the sequential appearance of MHC class IIhi CD86hi DCs in the airway mucosa and subsequently the PTLN, these findings are consistent with onward migration of OVA-presenting DCs from the site of antigen deposition in the airway to the draining lymph node. Although it is likely that such migrating DCs might be responsible for the transient peak of OVA-specific APC activity observed in the PTLN (Fig. 4 B), the possibility that airway-derived DCs may pass on antigen to their lymph node counterparts (which in turn become activated) cannot be excluded. In the experiments shown in Fig. 4 C we demonstrate that the in vitro APC activity of the airway DCs sampled at 2 h after OVA exposure can be partially blocked by mAb against the costimulator CD86. The efficiency of this blockade ranged from 25 to 55%.

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