ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance

Background: Costimulatory molecules like ICOS are important for the activation and differentiation of T lymphocytes upon allergen contact and thereby strongly affect the decision between the maintaining of tolerance or development of allergic immune response.

Methods: Three independent approaches were used to investigate the role of ICOS-mediated costimulation in the development of respiratory tolerance. First, WT mice received anti-ICOSL mAb or control mAb and were tolerized afterwards by intranasal application of OVA. Second, respiratory tolerance was induced in ICOS-deficient and WT mice. Third, tolerized Treg from ICOS-deficient and WT mice were transferred into pre-sensitized recipients. Subsequently, all mice were referred to an asthma model.

Results: Interruption of the ICOS/ICOSL interaction, either in ICOS-/- mice and by application of blocking anti-ICOSL mAb in WT mice, severely inhibited the development of respiratory tolerance, indicated by enhanced eosinophilic airway inflammation, mucus hypersecretion and increased Th2 cytokine secretion by lymph node cells in response to OVA-sensitization. Induction of respiratory tolerance was associated with a significantly increase in the number of CD4+Foxp3+ Treg cells in the lung and spleen of WT, but not ICOS-/- mice. Functional defects of Treg derived from ICOS-/- mice were shown by transfer into pre-sensitized recipients. ICOS-/- Treg were unable to suppress Th2 cytokine production and to induce protection in the recipients, demonstrating the importance of ICOS signalling for Treg cell function in the development of respiratory tolerance.

Conclusion: ICOS-mediated signalling plays a crucial role for the generation and the suppressive capacity of Treg cells mediating respiratory tolerance and protection from the development of an allergic phenotype.