Cbl-b Acts as a Gatekeeper to Control OVA-Induced Lung Inflammation

Abstract

As an E3 ubiquitin ligase and molecular adaptor, Cbl-b controls the activation threshold of the antigen receptor and negatively regulates CD28 co-stimulation, functioning as an intrinsic mediator of T cell anergy that maintains the balance between tolerance, activation, and autoimmunity. The role of Cbl-b in allergic airway inflammation is unclear. To determine the contribution of Cbl-b in tolerence to aeroallergens, we examined ovalbumin (OVA)-induced lung inflammation in Cbl-b-/- mice. Cbl-b-/- mice and wild type (WT) C57BL/6 mice were sensitized and challenged with OVA intranasally, a protocol that induces tolerance in WT mice. After challenge we analyzed lung histology, BAL cell recovery/differential, cytokine and chemokine expression, and airway hyperresponsiveness (AHR). We also determined cytokine production by cells of peritrachea lymph node/spleen after re-stimulation with OVA. Compared with WT mice, OVA challenged Cbl-b-/- mice (OVA-Cbl-b mice) showed significantly increased neutrophilic and eosinophilic infiltration into the lung and enhanced AHR. The levels of IgG2a and IgG1, but not IgE, were increased in the serum of OVA-Cbl-b mice. The levels of inflammatory mediators IFN-γ, IL-10, IL-12, IL-13, IP-10, MCP-1, MIP-1α, EOTAXIN, and RANTES were elevated in the BAL of OVA-Cbl-b mice. Lymphocytes from OVA-Cbl-b mice released increased amount of IFN-γ, IL-10, IL-13, and IP-10 in response to OVA stimulation. These results demonstrate that Cbl-b deficiency leads to break of tolerance to OVA in the murine airways, suggesting that Cbl-b may play a critical role in maintaining the lung homeostasis upon environmental exposure to allergens.