Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

• Published in: The Journal of immunology (1950) Vol. 164; no. 10; pp. 5177 - 5183
• Main Authors: van der Veen, Roel C, Dietlin, Therese A, Hofman, Florence M, Pen, Ligaya, Segal, Brahm H, Holland, Steven M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.05.2000
• Subjects: Adjuvants, Immunologic - genetics; Adjuvants, Immunologic - physiology; Animals; Cells, Cultured; Coculture Techniques; Encephalomyelitis, Autoimmune, Experimental - enzymology; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Immunosuppressive Agents - antagonists & inhibitors; Immunosuppressive Agents - pharmacology; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Proteins; Myelin-Associated Glycoprotein - immunology; Myelin-Oligodendrocyte Glycoprotein; NADPH oxidase; NADPH Oxidases - genetics; NADPH Oxidases - physiology; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - metabolism; Nitric Oxide - physiology; Superoxides - metabolism; Superoxides - pharmacology; T-Lymphocytes, Helper-Inducer - immunology; Tetradecanoylphorbol Acetate - antagonists & inhibitors; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.10.5177

NO, which suppresses T cell proliferation, may be inactivated by superoxide (O2-) due to their strong mutual affinity. To examine this possibility, preactivated Th clones were cocultured with stimulated macrophages. PMA neutralized the inhibitory activity of NO, which was dependent on extracellular O2- production. In contrast, macrophages from p47phox -/- (pKO) mice, which lack functional NADPH oxidase, retained their NO-dependent inhibition of T cell proliferation upon stimulation with PMA, indicating that NADPH oxidase is the major source of NO-inactivating O2- in this system. To examine the NO-O2- interaction in vivo, the role of NADPH oxidase in experimental 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 disease 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 mice and that in normal spleens inhibition of T cell proliferation by NO may be prevented by simultaneous NADPH oxidase activity.