Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.
Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.
Akbari
Omid
O
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, USA.
Freeman
Gordon J
GJ
Meyer
Everett H
EH
Greenfield
Edward A
EA
Chang
Tammy T
TT
Sharpe
Arlene H
AH
Berry
Gerald
G
DeKruyff
Rosemarie H
RH
Umetsu
Dale T
DT
D000485:Allergens; D000818:Animals; D000941:Antigens; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D001249:Asthma / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000633:toxicity; D011506:Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D000485:Allergens; D000941:Antigens; D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D011506:Proteins; D016753:Interleukin-10; D010047:Ovalbumin