Sa1761 Anti-TNF Therapy Switches on CD39+ FoxP3 Tregs in Association With Symptomatic and Endoscopic Remission in IBD

BACKGROUND & AIMS: Interferon gamma (IFNγ) responses and distinct CD8+ T cell transcriptional signatures can be linked to clinical manifestations of inflammatory bowl disease (IBD). CD39 is an ectonucleotidase and is typically associated with CD4+ T regulatory memory cells, which have the capacity to generate immunosuppressive adenosine. However, immunomodulatory effects of CD39 expression on CD8+ T cells, as in IBD, remain unknown. METHODS:CD39+CD8+ T cells were purified from peripheral blood (PB) and lamina propria (LP) of patients with Crohn's disease. Phenotypic features and functions of CD39+CD8+ T cells were assessed by flow cytometry and immunoblotting. RESULTS: CD39 expressing CD8+ T cells of patients with Crohn's disease are IFNγ-producing cells, and exhibited type 1 CD8+ T cell (Tc1) properties. CD3 and CD28-mediated synergistic stimulation of CD8+ T cells augment CD39 expression, boost reactive oxygen species (ROS) generation, and increase IFNγ production. CD39+CD8+ T cells preferentially express CD28, and exhibit robust ROS-JNK/NFkB signals and IFNγ production. Decreases in ROSmediated by inhibitors of NADPH oxidases (NOX) or knockdown of gp91phox (NOX2) in CD8+ T cells abrogate effects of TCR ligation, and decrease both CD39 expression and IFNγ production. Curiously, CD39+CD8+ T cells inhibit IFNγ production by CD39-CD8+ T cells via generation of adenosine, which is operational via the paracrine expression of Adenosine 2A (ADORA2A) receptor. CONCLUSIONS: CD8+ Tc1 cells express CD39, which is further boosted by cell activation and ROS, which in turn limit IFNg responses by these cells. Strategies to regulate ROS signal cascades and adenosine-mediated effects might have therapeutic potential in the treatment of Crohn's disease.