The Neurotrophic Factor Neuritin Maintains and Promotes the Function of Regulatory T cells in Autoimmunity and Cancer

Abstract

Abstract Regulatory T cells (Tregs) enforce immune homeostasis and self-tolerance and inhibit both natural and induced anti-tumor immunity. Consequently, there is considerable interest in therapeutic Treg enhancement or blockade to treat inflammatory/autoimmune diseases and cancer, respectively. Targeting Tregs requires a comprehensive understanding of the factors important for their maintenance, differentiation and function. Here we report that neuritin, a conserved, gpi-anchored molecule important for the development, survival and function of neurons, is highly expressed by induced and natural Tregs. Furthermore, neuritin expression was found to promote the maintenance of the Treg pool by stabilizing Foxp3 expression and promoting the persistence of these cells. Knockout of the neuritin gene in Tregs or anti-neuritin antibody treatment mitigated both Treg-dependent inhibition of colitis and resolution of experimental autoimmune encephalitis. Also, tumors grew poorly in Nrn1−/− mice, which mobilized more robust anti-tumor immunity than their wild type litter mates evidenced by elevated IFNgamma production and reduced PD1 expression. Importantly, we also found that in Tregs, neuritin expression was closely linked to the functional differentiation of Tregs into an activated, peripheral tissue-homing phenotype. As such, neuritin deficiency resulted in an imbalance between “central”- and “effector”-like Treg populations and functions. These findings characterize this neurotrophin as a hitherto unappreciated immunoregulatory molecule and a potential target for therapies aimed at the fine-tuning of Treg function in cancer and inflammatory/autoimmune diseases.