Redox Remodeling Allows and Controls B-Cell Activation and Differentiation

Abstract

During their differentiation to antibody-secreting plasma cells, B lymphocytes undergo dramatic changes in metabolism, structure, and function. Here we show that this transition entails extensive intra- and extracellular redox changes. Lipopolysaccharide (LPS)-driven activation and differentiation of naïve murine B splenocytes is paralleled by increased production of reactive oxygen species (ROS) from different sources, followed by a strong antioxidant response. This response includes upregulation of thioredoxin and of the cystine transporter xCT, and increased production and extracellular release of nonprotein thiols, mainly glutathione (GSH) and cysteine. Although ROS levels are higher in late-differentiating B cells, an early oxidative step is likely required to start the differentiation program, because inhibition of NADPH oxidase-dependent early ROS production impairs B-cell activation and differentiation. Addition of reducing agents such as 2-ME results in increased IgM secretion per cell, suggesting that the antioxidant response not only is aimed at restoring the redox homeostasis but also plays a functional role. A highly reduced environment coincident with the presence of large ROS-producing cells is observed in histologic sections of spleens from immunized mice, indicating that the redox modifications observed in LPS-induced B-cell differentiation in vitro occur also in vivo during physiologic immune responses.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…Trx upregulation is observed in murine splenic B lymphocytes following the initial oxidative burst (24). Conversely, inhibition of the Trx system impairs the mitogenic response of mouse splenocytes (25), favors ASK1-mediated cell death of CD4 + T lymphocytes (26), and downregulates costimulatory CD27 and CD28 molecules in T cells (26,27).…”

Relationship Between Redox Status and Cell Fate in Immunity and Autoimmunity

“…In particular, during early T-cell activation, the Nox dual oxidase 1 (DUOX1) generates H 2 O 2 that transiently inactivates TCR-associated phosphatases and acts in a positive feedback loop to enhance and sustain further TCR signaling (96). Similarly, B-cell receptor (BCR) engagement triggers ROS production that potentiates signal transduction (182). Thus, ROS may have a profound regulatory effect on lymphocytes through the reversible oxidation and consequent inhibition of PTP which are known to modulate TCR and BCR signaling (141).…”

Hyperactivity of the Ero1α Oxidase Elicits Endoplasmic Reticulum Stress but No Broad Antioxidant Response

“…Moreover, overexpression of xCT rescues GSH deficiency in cells devoid of ␥-glutamylcysteine synthase, which catalyzes the rate-limiting step in GSH synthesis (60). During B-cell differentiation, where an increased production of H 2 O 2 originating from various sources is observed, xCT is up-regulated as part of a broad antioxidant response (61).…”