Role Of Cd8+Effector Memory T Cell-Derived Il-6 In The Development Of Airway Hyperresponsiveness And Inflammation

RATIONALE: CD8+ effector memory T cells (Teff) restore airway hyperresponsiveness (AHR) and inflammation in CD8-deficient (CD8-/-) mice (Nat Med 2004:865), and was dependent on CD4+IL-4+ T cells (J Immunol 2007:2787). IL-6 is important for T helper cell differentiation and allergic asthma. (Nat Med 2008:565). We investigated the role of IL-6 in CD8+ Teff cell-mediated AHR and inflammation. METHODS: CD8+ Teff cells were differentiated in culture with IL-2 or IL-2 plus IL-4. IL-6 mRNA levels were evaluated by real-time PCR. Cellular content and protein levels of IL-6 were assessed by intracellular staining and ELISA, respectively. In vivo, CD8+ Teff cells were adoptively transferred into OVA-sensitized CD8-/- mice before challenge. IL-6 neutralizing antibody was given during the challenge phase. 48 hrs after the last challenge, AHR and eosinophilic inflammation were evaluated. RESULTS: IL-6 mRNA levels, cellular content, and protein levels increased in CD8+ Teff cells after culture with IL-2 plus IL-4, when compared to CD8+ Teff cells cultured with IL-2 alone. In vivo, recipients of adoptively transferred CD8+ Teff cells, differentiated in the presence of IL-2, restored AHR and eosinophilic inflammation. Following treatment with IL-6 antibody, CD8+ Teff cells failed to restore AHR. IFN-γ levels in the BAL were increased in the recipients of anti-IL-6. Intracellular staining of recovered lung CD8+ T cells after allergen challenge demonstrated their ability to produce IL-6. CONCLUSIONS: These data demonstrate that CD8+ Teff cells are an important source of IL-6 which appears essential in triggering of AHR. Their ability to produce IL-6 appears dependent on IL-4.