Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

Blocking HVEM–LIGHT interactions on T cells reduces the persistence of antigen-specific memory T cell populations after secondary expansion through decreased Akt activity and loss of Bcl-2 expression

Asthma-associated allergen Alternaria induces STAT6 dependent epithelial FIZZ1 that promotes airway fibrosis

Alternaria is a fungal allergen whereby sensitization to it serves as a risk factor for the development, persistence, and severity of asthma. Naïve WT C57/B6 mice received one intranasal challenge with Alternaria, Candida, or Aspergillus allergen extracts and airway eosinophil numbers analyzed 24 hours later. RNA from airway epithelial cells was processed for gene microarray analysis. Lung cells from naïve WT and collagen-1 GFP mice were incubated with rFIZZ1, stained for cell type, and analyzed by FACS. Mice received rFIZZ1 repetitively and airway eosinophils and lung histology were analyzed. Finally, WT and STAT6-/- bone marrow chimeric mice were challenged with Alternaria and airway eosinophil levels determined. Only naïve mice that received one Alternaria challenge developed significant airway eosinophilia. Gene microarray analysis of airway epithelial cells demonstrated that Alternaria-challenged WT mice had an over 20-fold increase in expression of "Found in Inflammatory Zone 1" (FIZZ1/Retnla). Epithelial FIZZ1 and BAL eosinophils were reduced in STAT6-deficient, but not PAR-2-deficient mice. rFIZZ1 displayed binding to CD45⁺CD11c⁺ (macrophages and dendritic cells) and collagen -1 producing CD45⁻ cells (fibroblasts). Administration of rFIZZ1 to naïve WT mice led to airway eosinophilia, peribronchial fibrosis, and increased thickness of the airway epithelium. Irradiated WT mice that received STAT6- deficient bone marrow showed reduced airway eosinophils after Alternaria challenge compared with irradiated STAT6- deficient mice that received WT bone marrow. Alternaria induces acute airway eosinophilia dependent on STAT6 expressed in hematopoetic cells. Epithelial FIZZ1 expression is induced by Alternaria that binds to collegen -1 producing cells and promotes airway fibrosis and epithelial thicknes

RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R.

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R