Superoxide prevents nitric oxide-mediated suppression of helper T lymphocytes: Decreased autoimmune encephalomyelitis in nicotinamide adenine dinucleotide phosphate oxidase knockout mice

NO, which suppresses T cell proliferation, may be inactivated by superoxide (O-2(-)) due to their strong mutual affinity. To examine this possibility, preactivated Th clones were cocultured with stimulated macrophages. PMA ne utralized the inhibitory activity of NO, which aas dependent on extracellul ar O-2(-) production. In contrast, macrophages from p47(phox -/-) (pKO) mic e, which lack functional NADPH oxidase, retained their NO-dependent inhibit ion of T cell proliferation upon stimulation with PMA, indicating that NADP H oxidase is the major source of NO-inactivating O-2(-) in this system. To examine the NO-O-2(-) interaction in vivo, the role of NADPH oxidase in exp erimental autoimmune encephalomyelitis was studied in pKO mice. No clinical or histological signs were observed in the pKO mice. Neither a bias in Th subsets nor a reduced intensity of T cell responses could account for the d isease resistance. Although spleen cells from pKO mice proliferated poorly in response to the immunogen, inhibition of NO synthase uncovered a normal proliferative response, These results indicate that NO activity may play a critical role in T cell responses in pKO mite and that in normal spleens in hibition of T cell proliferation by NO may be prevented by simultaneous NAD PH oxidase activity.