Project #1? ? Diseases characterized by persistent Th2 cytokine responses, such as asthma and chronic helminth infections, are associated with the development of significant tissue remodeling. Recent studies established a critical role for IL-13 in pulmonary remodeling associated with asthma. Although IL-10 has been shown to suppress Th2-driven inflammation, paradoxically,IL-10-/- mice have been shown to develop decreased airway hyperreactivity and mucus hyperplasia following airway allergen challenge. Interestingly, we found that the reduced pathological responses in IL-10-/- mice were associated with increased IL-13Rα2 production. Therefore, to determine whether the observed changes in IL-13Rα2 expression were responsible for the modified pathological responses in IL-10-/- mice, we generated IL-10-/-IL-13Rα2-/- double-KO (dKO) mice. The results from these studies showed that many of the pathological changes associated with persistent Th2 responses in the lung are inhibited by the actions of the IL-13 decoy receptor. IL-10 and IL-13Rα2 were both upregulated during acute and chronic Th2 responses, and mice genetically deficient inIL-10 and IL-13Rα2 (dKO mice) developed significantly exacerbated pathology. In contrast to IL-10/ mice, the dKO mice developed significant AHR and goblet cell hyperplasia following allergen exposure in the lung. The dKO mice also developed more fibrosis. Thus, these studies revealed that IL-10 and IL-13Rα2 are both required to restrain Th2-dependent inflammation and to prevent development of downstream immunopathologies. Indeed, these data identified distinct but cooperative roles for IL-10 and IL-13Rα2 in the suppression of Th2-dependent pathology. Their mechanisms of action, however, appear to be unique, with IL-10 controlling CD4+ Th2 cell development and inflammation and IL-13Rα2 regulating IL-13 effector responses, including AHR, mucus secretion, and fibrosis. These findings likely explain the confusing literature regarding the function of IL-10 in Th2 immunity, since few studies considered the important contribution of the IL-13 decoy receptor. From these studies, we discovered that Th2-mediated inflammation does not always correlate with the development of significant pathology and that targeting specific mediators, such as IL-13 or its receptors, may curtail or even prevent immune-mediated pathologies while allowing inflammation to continue. They also illustrate how the activities of IL-10 and IL-13Rα2 might be exploited in the treatment of a variety of Th2-driven diseases, including asthma, ulcerative colitis, and chronic helminth infections (Wilson MS, J Clin Invest, 2007).? ? Project #2? ? Dysfunctional regulatory T cells have been identified in allergic individuals and glucocorticoid-resistant patients, implying that this defect contributes to the development of atopy and subsequent Th2-driven allergic disorders. Successful immunotherapy and treatment of allergic individuals often correlate with an increase in Tregs, supporting the notion that Tregs are central regulators of allergic reactivity and Th2 responses more generally. Several studies in mice have illustrated a significant contribution by regulatory T cells in restraining pulmonary inflammation and preventing immune-mediated pathology, including fibrosis, following exposure to aeroallergens. Recent studies demonstrated that while IL-2 is not required for thymic Treg development, it is essential for optimal extrathymic Treg homeostasis. These studies tie together observations made in IL-2/ mice and endogenous Treg deficient (Foxp3/) mice, both of which succumb to hyper-proliferative autoimmune disorders. Thus, although IL-2 was previously considered a pan-T cell growth factor, contrasting functions are emerging, with IL-2 possibly playing a more critical role in tolerance via the maintenance/induction of regulatory T cell populations. Using several airway allergy systems, we examined whether IL-2 in complex with anti-IL-2 mAb could boost CD4+ Treg frequencies, with the aim of suppressing allergen-induced airway inflammation through Treg expansion. We found that recombinant IL-2 administered alone exacerbates airway inflammation, however, IL-2 administered as a complex with anti-IL-2 mAb significantly reduced airway inflammation and hyperreactivity. Whether IL-2:anti-IL-2 complexes were administered prior to airway challenge or therapeutically after airway inflammation, a significant reduction in airway pathology was observed. Both natural (Foxp3+) and inducible (IL-10gfp+) regulatory T cell populations increased following IL-2:anti-IL-2 treatment, and through the use of reconstituted RAG2/ mice we demonstrated that IL-10-producing Tregs are a critical population regulating airway allergy following IL-2:anti-IL-2 treatment. This study builds upon advances in Treg immunobiology and the regulation of allergic airway inflammation and presents a novel strategy of IL-2:anti-IL-2 complexes to expand endogenous IL-10-secreting Tregs, which can control Th2-mediated airway pathologies, such as AHR, mucus production, and fibrosis.
