Cbl-b Regulates Airway Mucosal Tolerance to Aeroallergen

Abstract

P>Background As an E3 ubiquitin ligase and a molecular adaptor, Cbl-b controls the activation threshold of the antigen receptor and negatively regulates CD28 costimulation, functioning as an intrinsic mediator of T cell anergy that maintains tolerance. However, the role of Cbl-b in the airway immune response to aeroallergens is unclear. Objective To determine the contribution of Cbl-b in tolerance to aeroallergens, we examined ovalbumin (OVA)-induced lung inflammation in Cbl-b-deficient mice. Methods Cbl-b-/- mice and wild-type (WT) C57BL/6 mice were sensitized and challenged with OVA intranasally, a procedure normally tolerated by WT mice. We analysed lung histology, bronchoalveolar lavage fluid total cell counts and differential, cytokines and chemokines in the airway, and cytokine response by lymphocytes after re-stimulation by OVA antigen. Results Compared with WT mice, OVA-challenged Cbl-b-/- mice showed significantly increased neutrophilic and eosinophilic infiltration in the lung and mucus hyperplasia. The serum levels of IgG2a and IgG1, but not IgE, were increased. The levels of inflammatory mediators IFN-gamma, IL-10, IL-12, IL-13, IP-10, MCP-1, MIP-1 alpha, eotaxin, and RANTES, but not IL-17A or IL-6, were elevated in the airway of Cbl-b-/- mice. Lymphocytes from Cbl-b-/- mice released increased amount of IFN-gamma, IL-10, IL-13, and IP-10 in response to OVA re-stimulation. However, no significant changes were noted in the CD4+CD25+ T regulatory cell populations in the lung tissues after OVA stimulation and there was no difference between WT and Cbl-b-/- mice. Conclusion These results demonstrate that Cbl-b deficiency leads to a breakdown of tolerance to OVA allergen in the murine airways, probably through increased activation of T effector cells, indicating that Cbl-b is a critical factor in maintaining lung homeostasis upon environmental exposure to aeroallergens.