Thymic stromal lymphopoietin programs the “allergy code” in dendritic cells

抄録

Thymic stromal lymphopoietin (TSLP) is recently implicated as a key molecule for initiating allergic inflammation at the epithelial cell-dendritic cell (DC) interface. TSLP is produced predominantly by epithelial cells, and induces the production of multiple chemokines and cytokines by several innate cell types such as DCs, mast cells, eosinophils, and NKT cells, contributing to the innate phase of allergic inflammation. However, its function is more prominent in the DC-mediated adaptive phase of allergic inflammation. TSLP-activated myeloid DCs (mDCs) can promote naïve CD4⁺ T cells to differentiate into a Th2 phenotype. We analyzed the signal transduction mechanisms of TSLP in human primary mDCs and found that it potently transduces a unique Th2-inducing compound signal in DCs. Whereas activation of nuclear factor κB (predominantly p50) drives DCs to produce OX40L to induce Th2 differentiation, the activation of signal transducer and activator of transcription 6 (STAT6) triggers DCs to secrete chemokines necessary for the recruitment of Th2 cells. In addition, TSLP signaling limits the activation of STAT4 and interferon regulatory factor 8 (IRF8), which are essential factors for the production of the Th1-polarizing cytokine interleukin-12. Because TSLP can be a rational therapeutic target for the treatment of allergic disorders, elucidating the mechanisms that regulate TSLP expression and the effects of TSLP on orchestrating the immune response toward a Th2 phenotype is essential for developing anti-TSLP therapy.