BTN2A2-Ig protein inhibits the differentiation of pathogenic Th17 cells and attenuates EAE in mice.

Pathogenic Th17 cells play a key role in the pathogenesis of many autoimmune diseases. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the commonly used animal model for human MS and is characterized by autoreactive CD4+T cells attacking autoantigens in the CNS and causing myelin sheath damage. Although the recombinant BTN2A2-IgG2aFc (BTN2A2-Ig) fusion protein has been shown to inhibit T cell functions in vitro, it's unclear whether BTN2A2-Ig affects pathogenic Th17 cells and EAE development. We show here that BTN2A2-Ig protein attenuates established EAE, as compared with control Ig protein treatment. This is associated with reduced activation and proliferation of T cells in BTN2A2-Ig-treated EAE mice. Furthermore, BTN2A2-Ig protein inhibits the differentiation of CD4 naïve T cells into pathogenic Th17 cells and reduces the expression levels of Th1/Th17 cytokines and the Th1/Th17 pathway related genes and proteins but increases the expression levels of Th2-related genes and proteins. Our studies not only provide new insights into the mechanisms by which BTN2A2-Ig affects T cells, but also have the potential to provide a new strategy to treat MS and other autoimmune diseases.

BTN2A2 protein negatively regulates T cells to ameliorate collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by persistent inflammatory responses in target tissues and organs, resulting in the destruction of joints. Collagen type II (CII)-induced arthritis (CIA) is the most used animal model for human RA. Although BTN2A2 protein has been previously shown to inhibit T cell functions in vitro, its effect on autoimmune arthritis has not been reported. In this study, we investigate the ability of a recombinant BTN2A2-IgG2a Fc (BTN2A2-Ig) fusion protein to treat CIA. We show here that administration of BTN2A2-Ig attenuates established CIA, as compared with control Ig protein treatment. This is associated with reduced activation, proliferation and Th1/Th17 cytokine production of T cells in BTN2A2-Ig-treated CIA mice. BTN2A2-Ig also inhibits CII-specific T cell proliferation and Th1/Th17 cytokine production. Although the percentage of effector T cells is decreased in BTN2A2-Ig-treated CIA mice, the proportions of naive T cells and regulatory T cells is increased. Furthermore, BTN2A2-Ig reduces the percentage of proinflammatory M1 macrophages but increases the percentage of anti-inflammatory M2 macrophages in the CIA mice. Our results suggest that BTN2A2-Ig protein has the potential to be used in the treatment of collagen-induced arthritis models.