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.

*There was an error in the AOP version of this article. The sentence in the abstract that read The T_R cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mouse T_R cells, blocked the development of AHR was worded incorrectly. The following sentence is correct: 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. This has been corrected in the HTML and the PDF. We regret this error.