Study of the role of the cytokine osteopontin in type-2 allergic responses

Abstract

Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease, as well as its effects on primary versus secondary antigenic encounters and its role in antigenic peripheral tolerance, remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These opposing effects of Opn-s are mainly mediated by regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected from allergic disease.Our data demonstrated the anti-inflammatory role of Opn in TH2-type allergic airway responses. Furthermore Opn is also highly expressed in activated Foxp3+ Tregs. Thus, we also investigated whether Opn had an impact on peripheral tolerance. Opn-deficient mice were impaired in mounting antigenic tolerance against a TH2-driven asthma model disease, while administration of rOpn had the opposite effect. rOpn promoted tolerance by expansion of suppressive plasmacytoid dendritic cells (pDCs) and expansion of Foxp3+ Tregs. In fact, rOpn was a pDC survival factor that instructed these cells to generate Treg cells, and also promoted the expansion of Foxp3+ Tregs. Overall, these novel effects on TH2 allergic responses and peripheral tolerance, place Opn as an important therapeutic target and a key cytokine controlling peripheral tolerance, and thus provide new insight into its role in immunity.