Regulation of Th2 and Tfh cell responses during allergic lung inflammation via STAT3

Abstract

Understanding the developmental mechanisms of adoptive immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Allergic lung inflammation entails both humoral immunity and cell-mediated type 2 responses. T helper 2 (Th2) cells trigger the activation of IgE producing B cells, mast cells and eosinophils. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by producing IL-21 and ICOS costimulation to activated B cells. It has been established that signal transducer and activator of transcription 3 (STAT3) plays essential roles during the differentiation of the T helper 17 (Th17) cells from naïve helper T cells. However, its role on Th2 responses to allergens remains incompletely understood. By employing T cell-specific STAT3 deficient mice, we demonstrated that STAT3 in T cells plays diverse role on Th2 cells depending on their locations in animal models of allergic asthma. In mediastinal lymph nodes (mLNs), STAT3-deficient T cells produced significantly reduced levels of Th2 cytokines. The frequencies of Th2 cells among CD4+ T cells in the lung were comparable between STAT3-suficient and STAT3-deficient T cells. By contrast, STAT3-deficient T cells in the airway exhibited significantly enhanced production of Th2 cell cytokines compared to STAT3-sufficient T cells. STAT3 signal in T cells is known to mediate the generation of Tfh cells as well as Th17 cells. We found that administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells in the mLNs against intranasal proteinase antigens. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE antibody production specific for the intranasal allergens. Co-transfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate the dynamic and opposing roles of STAT3 during the development of Th2 cells from mLNs to the airway and requirement of STAT3 for the generation of Tfh cells to intranasal antigen in the mLNs

thus, these results propose the need of careful consideration on STAT3-targeting approaches for the treatment of lung diseases.