Asthma is an inflammatory disorder of the conducting airways with abnormal airway hyper-responsiveness and remodeling, resulting in airflow restriction during breathing 
. Studies have found that immune function dysregulation is one of the key pathogenic mechanisms underlying airway allergic inflammation, in particular imbalance between Th2 cell and Th1 cell responses 
. More recently, another pivotal subset of CD4+
T cells (Treg cells), which have been related to control immune tolerance and subsequent autoimmune diseases, were also found to be important in suppressing allergic responses 
. For example, CD4+
Treg cells from grass pollen-allergic individuals were less able to suppress proliferative responses and IL-5 production by CD4+
T cells 
. Significant reduction of the CD4+
Treg cell frequency in peripheral blood was detected in patients with persistent or exacerbation of asthma when compared to control groups 
. In addition, Treg cells in patients with asthma were also decreased in bronchoalveolar lavage (BAL) fluid 
. In mouse asthma models, naturally occurring Treg (nTreg) cells are present in the lung tissue of sensitized mice and increase upon allergen inhalation. Inhibition of nTreg cells augments respiratory allergen-induced AHR and IgE production, as well as Th2 cytokine levels in BAL fluid 
. Therefore, cell therapy by replenishing functional Treg cells may be a new promising strategy for asthma prevention and treatment. It also have advantages by correcting the immune cell proportions and functions, which restore appropriate cytokine productions, compared to just targeting a single or a few cytokines produced by these dysregulated immune cells.
Treg cells can be either derived from the thymus (nTreg cells), or induced in the periphery in a TGF-β-dependent fashion (iTreg cells) 
. Both nTreg and iTreg cells share similar phenotypic characteristics and immune suppressive functions. nTreg cells are rare cell population so that it is difficult to obtain sufficient numbers of nTreg directly for the therapeutic need. Although repetitive expansion in vitro
is able to generate enough nTreg cells, recent study has indicated that the phenotypes and functional characteristics of the nTreg cells after the repetitive expansion have been altered 
. Moreover, intrinsic CD4+
nTreg cells are often defective in suppressing allergic immune responses in asthma patients, which limits the clinical use of these nTreg cells as autograft therapeutic agents. Our study has shown that iTreg cells are effective in both preventing and treating airway allergic responses, and that in vitro
induced-iTreg has a comparable anti-inflammatory activity to that of nTreg cells. iTreg cells may migrate to inflammatory sites in airways, and likely suppress Th1 and Th2 immune response directly or indirectly through inhibiting DC cells.
Induction of iTreg cells in vitro
not only avoids systemic application of cytokines and growth factors, but also generates an approach similar to an autograft, by which sufficient iTreg cells can be easily induced from the CD4+
cells in individual asthmatic patient in vitro
, and then adoptively transferred back to the same patient to induce immune tolerance to allergens and to suppress abnormal inflammatory responses in the airway without significant side effects. Moreover, iTreg cells also have several superior functional features compared to nTreg cells, including anti-apoptosis and resistance to Th17 conversion 
. Conversely, nTreg cells are more plastic and unstable under pro-inflammatory conditions 
. Therefore, adoptive transfer of iTreg cells may be a better approach as a novel cell therapy in airway allergic diseases.
Although many studies have demonstrated that adoptive transfer of iTregs can control lupus, colitis, gastritis and diabetes in animal models 
, it is unknown whether infusion of iTreg cells can attenuate airway allergic inflammation and improve respiratory function after asthma onset, We have now shown that adoptive transfer of iTreg cells before allergen challenge effectively prevented airway allergic inflammation and improved airway function in an OVA model. In addition to local relief of inflammation, abnormal systemic immune functions were also corrected to some extent. Of importance, the infusion of iTreg cells during allergen challenge still had significant effects on reducing lung inflammation and ARH, although to a less degree compared to iTreg cell administration prior to allergen challenge. The different efficacies between these two regimens can be caused with these possibilities. (1) Exogenous iTreg cells are more effective to attenuate the initiation of the inflammatory process, but less effective for the inflammation already occurred; (2) It needs certain time for infused iTreg cells to be effective, as all lung specimens were taken on day 28, regardless of when iTreg cells were given on day 22 before allergen challenge or on day 25 after first allergen challenge. Nevertheless, both iTreg and nTreg cells displayed the similar therapeutic effects on asthma progression. Mechanistically, Treg subset infusion regulates the local and systemic immune balance by increasing Treg and decreasing Th1/Th2 cell frequencies in the ongoing asthma.
In summary, adoptive transfer of in vitro induced iTreg cells is an effective way to both prevention and treatment of airway allergic disease, such as asthma, in a mouse OVA-asthma model, which will be a promising therapeutic approach for airway allergic diseases.