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 (TR) 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 TR cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS)–ICOS-ligand pathway. The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice,* TR 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 TR 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 TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mouse TR cells, blocked the development of AHR was worded incorrectly. The following sentence is correct: The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, TR cells blocked the development of AHR. This has been corrected in the HTML and the PDF. We regret this error.

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Figure 1: T-cell lines produce IL-10 when generated with IL-10-secreting DCs.
Figure 2: Development of IL-10-producing T cells in mice exposed to i.n. OVA.
Figure 3: TR cells regulate airway inflammation.
Figure 4: Effector function of regulatory T cells is dependent on IL-10 and ICOS.
Figure 5: ICOS costimulation is required for intranasal tolerance.
Figure 6: ICOS-L expression on DCs is required for i.n. tolerance.

Change history

  • 26 August 2002

    This was incorrect in AOP version but corrected in print. Changed one word in the abstract and moved a comma, as per the note.


  1. 1.

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


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This study was supported by the NIH Public Health Service (RO1HL62348, AI24571, AI26322, CA84500, AI39671, and AI38310), and a fellowship from the California Lung Association.

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Correspondence to Dale T. Umetsu.

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Akbari, O., Freeman, G., Meyer, E. et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8, 1024–1032 (2002) doi:10.1038/nm745

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