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

¹ Center for Clinical and Translational Science, Department of Biomedical Sciences, ² Department of Internal Medicine, and ³ Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Devendra K. Agrawal, Ph.D., Professor of Biomedical Sciences, Internal Medicine, and Medical Microbiology and Immunology, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178. E-mail: dkagr{at}creighton.edu

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–β and IL-10 mRNA transcripts and bronchoalveolar lavage fluid IL-10 and INF- 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–β, IL-10, IFN-, 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.

Key Words: airway hyperresponsiveness • forkhead winged helix transcription factor box P3 • inducible CD4⁺ CD25^– T-regulatory cells • naturally occurring CD4⁺CD25⁺ T-regulatory cells • programmed death-1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, which may result from an imbalance in the ratio of Th1 and Th2 cells, and a loss of function and/or absence of CD4+CD25+ T-regulatory cells. What This Study Adds to the Field Adoptive transfer of naturally occurring CD4+CD25+ T-regulatory cells and inducible CD4-CD25– T cells of lung and spleen tissue reversed allergic inflammation. This mechanism, at least in part, was due to increased expression of programmed death–1, and secretion of IL-10 and transforming growth factor–β.