Nitric Oxide Signaling in T Cell-Mediated Immunity

Nitric oxide (NO) is a key messenger in the pathogenesis of inflammation, linking innate and adaptive immunity. By targeting signaling molecules, NO from inducible NO synthase (iNOS) and endothelial (e)NOS affects T helper cell differentiation and the effector functions of T lymphocytes, and is a potential target for therapeutic manipulation. In this review we discuss the regulatory actions exerted by NO on T cell functions, focusing on S-nitrosylation as an important post-translational modification by which NO acts as a signaling molecule during T cell-mediated immunity. We also present recent findings showing novel mechanisms through which NO regulates the activation of human T cells, and consider their potential in strategies to treat tumoral, allergic, and autoimmune diseases. NO is a key regulator of adaptive immunity that influences both T cell activation and the fate decision programs that drive T helper cell differentiation and the development of allergic and autoimmune diseases. Important differences between the actions mediated by NO generated from either exogenous cellular sources or T lymphocytes, and between human and mouse species – with respect to the amount of NO produced and the regulation of NOS expression – can explain the dual actions exerted by NO in T cell-mediated adaptive immunity. The pathways through which NO regulates the response of T lymphocytes in adaptive immunity are expanding towards cGMP-independent mechanisms, including compartmentalized short-range protein S-nitrosylation. Recent studies have demonstrated that the production of NO is compartmentalized at the immune synapse of human T cells, and positively regulates T cell activation through S-nitrosylation-dependent mechanisms. Preclinical studies and clinical trials have opened new horizons for the application of NO sources and inhibitors to regulate T cell functions for the treatment of cancer and allergic and autoimmune diseases.