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-O2-) 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-O2- production increased during cognate T cell reactivation, while inhibition of EC-O2- by exogenous superoxide dismutase enhanced NO activity. By inhibiting NO, EC-O2- production promotes T cell expansion during peripheral immune-response activation, not during tissue inflammation.
van der Veen
Roel C
RC
Department of Neurology, University of Southern California Keck School of Medicine, MCH 142, 1333 San Pablo Street, Los Angeles, CA 90033, USA. vanderve@usc.edu
Dietlin
Therese A
TA
Karapetian
Armine
A
Holland
Steven M
SM
Hofman
Florence M
FM
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000503:physiopathology; D005110:Extracellular Space / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D063308:Myelin-Oligodendrocyte Glycoprotein; D019255:NADPH Oxidases / Q000235:genetics; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016877:Oxidants; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D019255:NADPH Oxidases