The Selenoprotein MsrB1 Instructs Dendritic Cells to Induce T-Helper 1 Immune Responses

Abstract

Immune activation associates with the intracellular generation of reactive oxygen species(ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidenceshows that ROS‐mediated signal transduction can be regulated by selenoproteins such asmethionine sulfoxide reductase B1 (MsrB1). However, how the selenoprotein shapes immunityremains poorly understood. Here, we demonstrated that MsrB1 plays a crucial role in the ability ofdendritic cells (DCs) to provide the antigen presentation and costimulation that are needed forcluster of differentiation antigen four (CD4) T‐cell priming in mice. We found that MsrB1 regulatedsignal transducer and activator of transcription‐6 (STAT6) phosphorylation in DCs. Moreover, bothin vitro and in vivo, MsrB1 potentiated the lipopolysaccharide (LPS)‐induced Interleukin‐12 (IL‐12)production by DCs and drove T‐helper 1 (Th1) differentiation after immunization. We propose thatMsrB1 activates the STAT6 pathway in DCs, thereby inducing the DC maturation and IL‐12production that promotes Th1 differentiation. Additionally, we showed that MsrB1 promotedfollicular helper T‐cell (Tfh) differentiation when mice were immunized with sheep red blood cells.This study unveils as yet unappreciated roles of the MsrB1 selenoprotein in the innate control ofadaptive immunity. Targeting MsrB1 may have therapeutic potential in terms of controllingimmune reactions.

Effect of Selenium and Peroxynitrite on Immune Function of Immature Dendritic Cells in Humans

“…Previous studies have indicated that selenium influences production of B cells and their resident antibodies, as well as the differentiation of T cells and macrophages across multiple species [ 19 – 22 ]. It has been suggested that the differentiation and immune function of chicken DCs can also be influenced by selenium [ 23 , 24 ]; moreover, high levels of organoselenium drugs like ebselen have been shown to inhibit DC-induced proliferation of T cells and secretion of cytokines [ 4 ]. In this study, human imDCs were exposed to different dosages of Na 2 SeO 3 and findings revealed that those below 0.1 μmol/L were capable of promoting proliferation.…”

“…To date, studies have indicated that both mitochondrial reactive oxygen species (ROS) and superoxide anions (O 2 − ) contribute to the development of DCs. For example, investigations in mice have reported that ROS activates DCs and promotes interaction between DCs and T cells during antigen presentation [ 4 ], as well as induces apoptosis or necrosis of DCs via Acinetobacter baumannii outer membrane protein A [ 5 ]. Among humans, ROS stimulates differentiation of mononuclear cells into DCs [ 6 ], and O 2 − assists in the maturation of imDCs into mDCs [ 7 ].…”

“…The effect of sodium selenite on the immune function of chicken DCs was recently studied [ 23 , 24 ]. In humans, however, studies have yet to clarify how physiological levels of selenium impact imDCs [ 4 , 23 , 24 ], especially under peroxynitrite conditions.…”

Reactive Oxygen Species in Autoimmune Cells: Function, Differentiation, and Metabolism

“…Protein oxidative modification state is regulated by balance between ROS and methionine sulfoxide reductase (Mrs). Mrsb1 deficiency in DC delays its maturation and decreases DC-induced Th1 differentiation, and is associated with defective differentiation of follicular helper T cell cells in vivo (81). Transforming growth factor β (TGF-β) is a cytokine with broad regulatory functions in T cell development and differentiation.…”

Methionine Sulfoxide Reductase B Regulates the Activity of Ascorbate Peroxidase of Banana Fruit

“…Previous studies on Msr have mainly focused on its role in resistance to oxidative stress in organisms [ 21 , 22 , 23 , 24 ], which is related to repair of oxidized proteins, such as GroEL [ 25 ], Fth [ 26 ], hERG [ 27 ], apolipoprotein A-I [ 28 ], CaMKII [ 29 ], TRPM6 channel [ 30 ], HypT [ 31 ], actin [ 32 ], CaM [ 33 , 34 ], GrpEL1/Mge1 [ 35 ], heme oxygenase [ 36 ], and high-density lipoprotein [ 37 ]. Growing evidence suggests that Msr may be implicated in the regulation of protein function by modifying the sulfoxidation of proteins in a similar manner to that of other protein modification, such as phosphorylation [ 38 , 39 , 40 , 41 ]. However, only a few potential targets of Msr in relation to sulfoxidation modification have been investigated in higher plants [ 23 , 34 , 42 ].…”