Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung
Kun He1,2,5, Angela Hettinga1,2,5, Sagar Laxman Kale2,3, Sanmei Hu2,3, Markus M. Xie4, Alexander L. Dent4, Anuradha Ray2,3 and Amanda C. Poholek1,2 *
1Division of Pediatric Rheumatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.; 2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.; 3Department of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh PA, 15213, USA.; 4Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202 USA.; 5These authors contributed equally: Kun He, Angela Hettinga
A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Using a murine model of house dust mite-mediated allergic asthma, we found Blimp-1 was required for inhaled but not systemically delivered allergens, suggesting a tissue-specific function for Blimp-1 to promote Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to upregulate Blimp-1 and promote Th2 cell development. These data reveal an unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.