Naturally occurring and inducible T-regulatory cells modulating immune response in allergic asthma

Halvor S. McGee, Devendra K. Agrawal

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Rationale: T-regulatory cells (Tregs) are potent immunomodulators in allergic asthma. Objectives:We evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4+CD25+ Tregs (NTregs) and CD4+CD25- inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroachsensitized and -challenged mice. Methods: GFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy. Measurements and Main Results: Adoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHRto methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4+CD25+ T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25-) and lung iTregs (L25-) groups. Higher levels of transforming growth factor-β and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-γ levels were observed in lung CD4+CD25+ cells from the L252 and S252 cell-recipient mice than from lung NTregs (L25-) and spleen NTregs (S25+) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels. Conclusions: Tregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4+ type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-β, IL-10, IFN-γ, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.

Original languageEnglish
Pages (from-to)211-225
Number of pages15
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume180
Issue number3
DOIs
StatePublished - Aug 1 2009

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Regulatory T-Lymphocytes
Asthma
Lung
Interleukin-10
Spleen
Green Fluorescent Proteins
Adoptive Transfer
Methacholine Chloride
Bronchoalveolar Lavage Fluid
Transforming Growth Factors
Inflammation
Cockroaches
Interleukin-13
Tracheostomy
Interleukin-5
Immunologic Factors
Interleukin-4
Lymph Nodes
T-Lymphocytes
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

Cite this

@article{3bc8bdf0098449b9a6d9de90a8ac59dd,
title = "Naturally occurring and inducible T-regulatory cells modulating immune response in allergic asthma",
abstract = "Rationale: T-regulatory cells (Tregs) are potent immunomodulators in allergic asthma. Objectives:We evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4+CD25+ Tregs (NTregs) and CD4+CD25- inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroachsensitized and -challenged mice. Methods: GFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy. Measurements and Main Results: Adoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHRto methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4+CD25+ T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25-) and lung iTregs (L25-) groups. Higher levels of transforming growth factor-β and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-γ levels were observed in lung CD4+CD25+ cells from the L252 and S252 cell-recipient mice than from lung NTregs (L25-) and spleen NTregs (S25+) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels. Conclusions: Tregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4+ type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-β, IL-10, IFN-γ, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.",
author = "McGee, {Halvor S.} and Agrawal, {Devendra K.}",
year = "2009",
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language = "English",
volume = "180",
pages = "211--225",
journal = "American Journal of Respiratory and Critical Care Medicine",
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TY - JOUR

T1 - Naturally occurring and inducible T-regulatory cells modulating immune response in allergic asthma

AU - McGee, Halvor S.

AU - Agrawal, Devendra K.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - Rationale: T-regulatory cells (Tregs) are potent immunomodulators in allergic asthma. Objectives:We evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4+CD25+ Tregs (NTregs) and CD4+CD25- inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroachsensitized and -challenged mice. Methods: GFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy. Measurements and Main Results: Adoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHRto methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4+CD25+ T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25-) and lung iTregs (L25-) groups. Higher levels of transforming growth factor-β and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-γ levels were observed in lung CD4+CD25+ cells from the L252 and S252 cell-recipient mice than from lung NTregs (L25-) and spleen NTregs (S25+) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels. Conclusions: Tregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4+ type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-β, IL-10, IFN-γ, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.

AB - Rationale: T-regulatory cells (Tregs) are potent immunomodulators in allergic asthma. Objectives:We evaluated the functional effects of Tregs by adoptively transferring naturally occurring CD4+CD25+ Tregs (NTregs) and CD4+CD25- inducible Tregs (iTregs) from lung and spleens of green fluorescent protein (GFP)-transgenic Balb/c mice into cockroachsensitized and -challenged mice. Methods: GFP-labeled NTregs and iTregs were adoptively transferred into cockroach-sensitized and -challenged mice. Airway hyperresponsiveness (AHR) to methacholine was examined using a single-chamber, whole-body plethysmograph and invasive tracheostomy. Measurements and Main Results: Adoptive transfer of either NTregs or iTregs from lung or spleen reversed airway inflammation and AHRto methacholine, and the effect lasted for at least 4 weeks. GFP-labeled iTregs up-regulated CD25 and forkhead-winged transcriptional factor box protein 3 and migrated to lymph node and lung. Lung CD4+CD25+ T cells isolated from each group of recipient mice were inducible costimulatory molecule-high and programmed death (PD)-1-positive; however, higher expression of PD-1 was found in the spleen iTregs (S25-) and lung iTregs (L25-) groups. Higher levels of transforming growth factor-β and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-γ levels were observed in lung CD4+CD25+ cells from the L252 and S252 cell-recipient mice than from lung NTregs (L25-) and spleen NTregs (S25+) cell-recipient mice. Adoptive transfer of either cell type significantly reduced bronchoalveolar lavage fluid IL-4, IL-5, and IL-13 levels. Conclusions: Tregs reverse AHR and airway inflammation; however iTregs that differentiated into IL-10-producing CD4+ type 1 cells in the lung exert their suppressive activity likely by higher levels of transforming growth factor-β, IL-10, IFN-γ, and elevated levels of PD-1 compared with NTregs. Hence, PD-1 may be a conduit for reversing AHR by Tregs and a plausible target for treating asthma.

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