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

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.