Naturally Occurring and Inducible T-regulatory Cells Modulating Immune Response in Allergic Asthma

Am J Respir Crit Care Med. 2009 Aug 1;180(3):211-25. doi: 10.1164/rccm.200809-1505OC. Epub 2009 May 15.

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 cockroach-sensitized 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 AHR to 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-beta and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF-gamma levels were observed in lung CD4(+)CD25(+) cells from the L25(-) and S25(-) 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-beta, IL-10, IFN-gamma, 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Asthma / immunology*
  • Asthma / metabolism
  • Asthma / pathology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Proliferation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Immune Tolerance
  • Immunity, Cellular / immunology*
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Cytokines