Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses

Abstract

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1) is a multifunctional protein possessing DNA repair, redox control, and transcriptional regulatory activities. Although Ape1/Ref-1 plays multiple roles in the immune system, its functions in helper T (Th) cell activation and differentiation are largely unknown. In this study, the function of Ape1/Ref-1 in Th cell activation was analyzed using an Ape1/Ref-1 redox-specific inhibitor, E3330. When splenocytes from OT-II mice, which are ovalbumin (OVA)-specific T-cell receptor transgenic mice, were activated with OVA in the presence of E3330, the induction of IFN-γ-producing OT-II T cells was significantly increased. In contrast, E3330 did not enhance IFN-γ production from plate-bound anti-CD3 antibody-stimulated CD4 T cells in the absence of antigen presenting cells (APCs). Furthermore, E3330-pretreated and OVA-pulsed APCs also enhanced the IFN-γ production from OT-II T cells. These results suggested that E3330 enhances Th1 responses by modifying APC function. E3330 did not alter the surface expression of MHC-II or the co-stimulatory molecules CD80 and CD86 on APCs. On the other hand, E3330 up-regulated the IL-12 p35 and p40 gene expression, and IL-12 surface retention, but decreased the IL-12 secretion from Toll-like receptor (TLR) ligand-stimulated APCs. These results were confirmed with Ape1/Ref-1 knockdown experiments. Taken together, our findings indicated that the suppression of Ape1/Ref-1 redox function leads to an increased cell surface retention of IL-12 and enhances Th1 responses. This is the first study to demonstrate that Ape1/Ref-1 modulates the IL-12 production and secretion from APCs and controls Th1 immune responses.

APE1 may influence CD4+ naïve T cells on recurrence free survival in early stage NSCLC

“…We speculate that the underlying mechanism involved might be due to the regulatory effects of APE1 on the function of CD4 + T cells. A study confirmed that APE1 can inhibit the release of IL-12 from antigen-presenting cells and thus diminish the T helper cell type 1 responses induced by IL-12 [ 15 ], and the authors strongly suggest that redox function of APE1 plays a major role in this process. Research has showed that transcription factors including members of the nuclear factor of activated T cell (NFAT), NF-κB, and activator protein-1 (AP-1) families are important during the process of T cells differentiation [ 31 ].…”

“…Studies of mesenchymal cells or tumor cells have demonstrated that surface adhesion receptors, such as CD44, plays an important role of in the migratory cycle of T cells [ 28 ], while APE1 can cleave CD44 mRNA in vitro studies through exhibiting its endonucleases function [ 29 ]. Moreover, the effect of APE1 on immune cells, such as T cells, B cells and monocyte macrophages, has also been widely studied [ 14 , 15 , 30 ]. Given the aforementioned findings, it is not surprising that APE1 was associated with the abundance of CD4 + T cells.…”

“…APE1 was found to be a regulatory protein to participate in macrophage inflammatory response through regulating TNF-α, IL-6 and IL-12 [ 14 ]. Another study showed that APE1 can regulate the production and secretion of IL-12 from antigen presenting cells and control helper T (Th) cells immune response [ 15 ]. In addition, it was found that APE1 also can be a “tuning molecule” to regulate the proliferation of B cells through activating CD40 pathway [ 16 ].…”

Fes-deficient macrophages enhance CD8+T cell priming and tumour control through increased proinflammatory cytokine production and presentation

“…This increase in cell-surface IL-12 may be partially responsible for improved T cell priming by fes -/-BMDMs. One group demonstrated that increased membrane-associated IL-12 improved DC-mediated priming of OT-II T cells, despite an apparent reduction in secreted IL-12 (55). This suggests that membrane-associated IL-12 may be more important than secreted IL-12 in stimulating T cells.…”

APE1/Ref-1 Role in Inflammation and Immune Response

“…The role of APE1 in adaptive immunity has been described in several studies (Figure 3). According to Akhter et al (109), the redox activity of APE1 is essential for T helper cell 1 (Th1) response through antigen-presenting cells. The authors observed that in splenocytes from OT-II mice stimulated with ovalbumin, treatment with E3330 increased IFN-g-producing T cells by altering functions of antigen-presenting cell, suggesting suppression of Th1 immune responses.…”