Extra-cellular superoxide promotes T cell expansion through inactivation of nitric oxide

The mechanism and regulation of immunosuppression by nitric oxide (NO) is unclear. Extra-cellular superoxide (EC-O 2 −) production by NADPH-oxidase (phox) may prevent NO-mediated suppression of T cell proliferation. p47 phox−/− mice are resistant to experimental allergic encephalomyelitis (EAE), coinciding with enhanced splenic NO activity, but no causal link was established. Here, we demonstrate such link, since p47 phox−/− mice developed severe EAE by adoptive transfer, but only if NO production during ex vivo donor cell reactivation was inhibited. EC-O 2 − production increased during cognate T cell reactivation, while inhibition of EC-O 2 − by exogenous superoxide dismutase enhanced NO activity. By inhibiting NO, EC-O 2 − production promotes T cell expansion during peripheral immune-response activation, not during tissue inflammation.