title: Naturally occurring and inducible T-regulatory cells modulating immune response in allergic asthma.
abstract: BACKGROUND
  T-regulatory cells (Tregs) are potent immunomodulators in allergic asthma.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Center for Clinical and Translational Science, Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: Halvor S
authors.initials: HS
authors.lastname: McGee
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007111:Immunity, Cellular / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines