Potential role of thioredoxin in immune responses in intestinal lamina propria T lymphocytes

Abstract

Thioredoxin (TRX) is a ubiquitous oxidoreductase with strong co-cytokine, chemoattractant and anti-apoptotic activities. TRX expression was found to be particularly elevated in the intestinal mucosa, where its physiologic function is entirely unknown. Here, we demonstrate a high level of TRX expression in lamina propria T cells (LP-T) as opposed to autologous peripheral blood T lymphocytes (PB-T). Addition of recombinant human TRX (rhTRX) to PB-T enhances TRX gene expression. This autoregulation involves the calcineurin signaling pathway, as rhTRX antagonizes the cyclosporine A (CsA)-and tacrolimus-mediated suppression of TRX gene expression. Similarly, rhTRX reverses the suppression of IL-2 mRNA production by CsA and enhances cytokine production preferentially in prestimulated cells. The differential TRX expression in LP-T versus PB-T may thus contribute to the high-level, CsA-resistant IL-2 production characteristic for CD2-stimulated LP-T. Inversely, inactivation of TRX in LP-T through inhibition of TRX reductase abolishes cytokine gene expression. TRX may play a key role in the specialized intestinal microenvironment in amplifying immediate immune responses of LP-T whenever appropriate costimulation of LP-T is provided. IntroductionThioredoxin (TRX) is a ubiquitous 12-kDa oxidoreductase containing two redox-active cysteine residues in its conserved active-center motif -Cys-Gly-Pro-Cys- [1,2]. Together with the selenoprotein TRX reductase and NADPH, it operates as a protein disulfide-reducing system [3][4][5][6][7][8]. Human PBMC express only minute amounts of TRX, which increase after mitogenic stimulation in vitro [3,9,10]. Oxidative stress through, e.g., hydrogen peroxide or after ischemia-reperfusion enhances the expression of TRX [11,12], which serves as an antioxidant in addition to intracellular glutathione [13][14][15]. Moreover, TRX is involved in the redox control of DNA binding of transcription factors like NF-jB [16,17] and AP-1 [18,19]. TRX stimulates cell growth [20] and is known as an autocrine growth factor for human T lymphotropic virus-1 and EBV-transformed lymphocytes [9]. TRX mediates anti-apoptotic effects [21][22][23], is a strong chemoattractant for neutrophils, monocytes, and T cells [24], and acts like a co-cytokine through stimulation of DNA synthesis in concert with IL-1 [9], IL-2 [4, 9], , and . TRX was suggested to enhance proliferation by increasing the cellular uptake of cystine into PBMC [27] and by sensitizing cells for growth factors [28].Upon stimulation, lymphocytes secrete TRX through a leaderless secretory pathway [29,30]. Extracellular TRX binds to the cell membrane without a high-affinity [25,32]. Because the gut is the largest immunologic organ of the body and harbors the largest T cell compartment (lamina propria), one could assume that TRX is involved in intestinal immune responses.The proliferative activity of lamina propria T lymphocytes (LP-T) towards TCR/CD3-dependent stimuli is extremely low in the normal gut, which may in part be explained by the inability of ...

Identification and Functional Analysis of Antifungal Immune Response Genes in Drosophila

“…These results indicate that genes involved in cytoskeletal and cell death regulation, along with spen (chromatin regulator) and JhI-21 (transporter induced by juvenile hormone), are generally required for phagocytosis of diverse microorganisms. In contrast, jumeaux and Trx-2 are required to specifically phagocytose S. aureus , which is known to utilize diverse immune evading mechanisms [29]–[31]. Therefore, hemocytes appear to require genes involved in diverse cellular functions to mediate a proper cellular immune response against fungal and bacterial infection.…”

Redox biology of the intestine

“…Trx-catalyzed reduction of disulfide bridges in hBD-1 enhances hBD-1 killing activity against commensal bacteria and opportunistic fungi, consistent with Trx function in innate immunity [110]. Unstimulated lamina propria T lymphocytes (LP-T) similarly exhibit high expression of Trx which contributed to the regulation of intracellular redox homeostasis in these cells [111]. In stimulated LP-T cells, constitutive as well as inducible Trx function as amplifiers of the inflammatory response by promoting and sustaining T-cell cytokine production [111].…”

“…Unstimulated lamina propria T lymphocytes (LP-T) similarly exhibit high expression of Trx which contributed to the regulation of intracellular redox homeostasis in these cells [111]. In stimulated LP-T cells, constitutive as well as inducible Trx function as amplifiers of the inflammatory response by promoting and sustaining T-cell cytokine production [111]. Potential Trx/TrxSS involvement in the etiology of intestinal disorders is a relevant topic in the redox pathobiology of the intestine that warrants further study.…”

“…LP-T activation and proliferation rely on a reducing extracellular environment that is provided by antigen presenting cells [191]; resident lamina propria macrophages are unable to secrete cysteine, and are therefore unable to stimulate LP-T [192]. Furthermore, ROS-mediated NF-κB-dependent activation of an pro-inflammatory response was attenuated by a constitutively higher Trx1 redox status in LP-T cells as compared to peripheral blood T cells [111]. Oxidative damage to the epithelia caused the recruitment of cysteine-secreting blood-borne macrophages which increased LP-T GSH levels and induced LP-T proliferation [190].…”

Nitrosothiols in the Immune System: Signaling and Protection

“…Trxs are expressed in primary T lymphocytes and T-cell lines, mainly upon mitogenic stimulation in the former (150,169,187), and Trx is particularly prominent in T lymphocytes of the intestinal lamina propria. These cells expressed more Trx than peripheral blood T cells (PBTs), and they produce more proinflammatory cytokines in response to activation stimuli (161). Moreover, in experimental studies, cytokine expression and endogenous Trx in activated PBTs increase after pretreatment with recombinant Trx.…”