Decreased STAT5 phosphorylation and GATA‐3 expression in NOX2‐deficient T cells: Role in T helper development

Abstract

Summary Absence of phagocyte NADPH oxidase (NOX2) activity causes chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent bacterial infections. In contrast to this innate immune deficit, CGD patients and animal models display predisposition to autoimmune disease and enhanced response to H. pylori and influenza infection. These data imply an altered, perhaps augmented, adaptive immune response in CGD. Previous data demonstrated functional NOX2 expression in T cells, and the goal was to determine if NOX2-deficient T cells are inherently altered in their responses. Activation of purified naive CD4+ T cells from NOX2-deficient mice led to augmented IFN-γ and diminished IL-4 production and an increased ratio of expression of the TH1-specific transcription factor T-bet versus the TH2-specfic transcription factor GATA-3, consistent with a TH1 skewing of naïve T cells. Selective inhibition of TCR-induced STAT5 phosphorylation was identified as a potential mechanism for skewed T helper differentiation. Exposure to anti-oxidants inhibited, while pro-oxidants augmented TH2 cytokine secretion and STAT5 phosphorylation, supporting the redox dependence of these signaling changes. These data suggest that TCR-induced ROS generation from NOX2 activation can regulate the adaptive immune response in a T cell inherent fashion, and propose a possible role for redox signaling in T helper differentiation.

TLR3-Triggered Reactive Oxygen Species Contribute to Inflammatory Responses by Activating Signal Transducer and Activator of Transcription-1

“…Recent studies have shown that CGD patients maintain an intact memory response in humoral immunity, with normal serum IgG and influenza-specific Ab levels, although they have reduced numbers of circulating CD27 + memory B cells (47). Moreover, NOX2-deficient T cells show a skewed Th1 response, with augmented IFN-g and decreased IL-4 production (48). These data collectively suggest that intact, and perhaps augmented, adaptive immune responses (i.e., humoral immunity and Th1 inflammatory responses) may compensate for the profound innate immune defect and contribute to enhanced responses to influenza virus infection in CGD patients and animal models.…”

Sequestosome1/p62: A regulator of redox-sensitive voltage-activated potassium channels, arterial remodeling, inflammation, and neurite outgrowth

“…In addition to responses to acute hypoxia, vascular remodeling following arterial injury is accompanied by regulated and time-dependent production of H 2 O 2 which plays a critical role in modulating inflammatory responses [96][97][98]. Shatynski et al recently show that T cell activation induces ROS generation via NADPH oxidase (NOX2), which is important in differentiation of naïve T cells to Th2 cells [147]. Activation of purified naïve CD4 + T cells from NOX2-deficient mice led to augmented IFN-γ and diminished IL-4 production and an increased ratio of expression of the Th1-specific transcription factor T-bet versus the Th2-specific transcription factor GATA-3 [147].…”

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

“…Th2 cell differentiation (Shatynski et al 2012). Interestingly, in murine models of NOD (non-obese diabetes) (Thayer et al 2011) or neglect-induced apoptosis (Purushothaman and Sarin 2009), T-cell-specific NOX2 was shown to be crucial for autoimmunity and CD4…”