NADPH Oxidase Deficiency Regulates Th Lineage Commitment and Modulates Autoimmunity

Abstract

Reactive oxygen species are used by the immune system to eliminate infections; however, they may also serve as signaling intermediates to coordinate the efforts of the innate and adaptive immune systems. In this study, we show that by eliminating macrophage and T cell superoxide production through the NADPH oxidase (NOX), T cell polarization was altered. After stimulation with immobilized anti-CD3 and anti-CD28 or priming recall, T cells from NOX-deficient mice exhibited a skewed Th17 phenotype, whereas NOX-intact cells produced cytokines indicative of a Th1 response. These findings were corroborated in vivo by studying two different autoimmune diseases mediated by Th17 or Th1 pathogenic T cell responses. NOX-deficient NOD mice were Th17 prone with a concomitant susceptibility to experimental allergic encephalomyelitis and significant protection against type 1 diabetes. These data validate the role of superoxide in shaping Th responses and as a signaling intermediate to modulate Th17 and Th1 T cell responses.

Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

“…Some investigators have argued for a critical role, in particular in later, effector processes (36)(37)(38), although others have cautioned about possible misinterpretations of findings from Th17 transfer experiments because of the conversion to or expansion of Th1 cells (39,40). In clear contradiction, IL-17-producing cells were found either to inhibit diabetes in NOD mice, as well as in BioBreeding rats, in several experimental contexts (41)(42)(43) or to have no effect (44). These divergent conclusions likely reflect multiple complexities: that different Th subsets may play variable roles according to the particular disease stage; that multiple cell types can produce IL-17; and that Th17 cells produce cytokines other than IL-17.…”

Identification of a region in p47phox/NCF1 crucial for phagocytic NADPH oxidase (NOX2) activation

“…A small induction of ROS has been detected earlier in blood granulocytes of BQ.Ncf1 m1J/m1J mice [22], and residual PMA-induced ROS production was also observed in neutrophils and macrophages of NOD.Ncf1 m1J mice [7]. Combined with the observation that the mutant protein is completely defective in activating NOX2, we conclude that the small inducible ROS production is not dependent on p47phox but can be derived from NOX2 activated by other mechanisms or cellular sources other than the NOX2 complex.…”

“…The size of the detected p47phox protein corresponded to the mRNA splice variant, which lacked 24 nt in the beginning of Exon 8, and this mRNA variant was concluded to be the only one expressed as protein, although at very low levels. A similar low-level expression of p47phox has since been reported in bone marrow macrophages of NOD.Ncf1 m1J mice [7]. NOX2-derived ROS are multifaceted regulators of the immune system [8].…”

“…A spontaneous single intronic nucleotide change in mouse Ncf1 has been reported to lead to decreased ROS production [4], which is clearly reduced in Ncf1 m1J/m1J mice, irrespective of the genetic background [5][6][7], but it is not known whether NOX2-dependent ROS production is blocked completely or just decreased to a background level of ROS from other cellular sources.…”

Th17 cell-Mediated Responses in Type 1 Diabetes Pathogenesis

“…In parallel, using NADPH oxidase deficient NOD mice, Tse et al showed that the lack of NADPH oxidase resulted in protection against T1D. The mechanism involved in this protection was the polarization of T cells to Th17 phenotype instead of Th1 pattern in NOD mice NADPH oxidase deficient, suggesting that Th1 cells are more pathogenic than Th17 cells in promoting T1D [78].…”