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Induction of Regulatory T Cells by Macrophages Is Dependent on Production of Reactive Oxygen Species

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Induction of Regulatory T Cells by Macrophages Is Dependent on Production of Reactive Oxygen Species Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species Marina D. Kraaija, Nigel D. L. Savageb, Sandra W. van der Kooija, Karin Koekkoeka, Jun Wangc, J. Merlijn van den Bergd, Tom H. M. Ottenhoffb, Taco W. Kuijpersd, Rikard Holmdahle, Cees van Kootena,1, and Kyra A. Geldermana,1 Departments of aNephrology, bInfectious Diseases, and cRheumatology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; dEmma Childrens Hospital, Amsterdam Medical Center, 1100 DD, Amsterdam, The Netherlands; and eMedical Inflammation Research, Karolinska Institute, 17177 Stockholm, Sweden Edited* by Johannes J. van Rood, Leiden University, Leiden, The Netherlands, and approved August 31, 2010 (received for review August 13, 2010) The phagocyte NAPDH–oxidase complex consists of several phago- than are their wild-type littermates (9, 10). This observation is in cyte oxidase (phox) proteins, generating reactive oxygen species line with observations in CGD patients. Interestingly, the reduced (ROS) upon activation. ROS are involved in the defense against ROS-producing capacity in our congenic rat model mediated microorganisms and also in immune regulation. Defective ROS for- higher susceptibility to pristane-induced arthritis in a T-cell– mation leads to chronic granulomatous disease (CGD) with in- dependent fashion (9, 11). However, T cells express no or only creased incidence of autoimmunity and disturbed resolution of very low levels of Nox2, suggesting that other cells determine the inflammation. Because regulatory T cells (Tregs) suppress autoim- T-cell response by producing ROS (12). One study, however, does mune T-cell responses and are crucial in down-regulating immune show low levels of Nox2 in T cells (13). Because antigen-presenting responses, we hypothesized that ROS deficiency may lead to de- cells (APC) interact with T cells during antigen presentation, and phox creased Treg induction. Previously, we showed that in p47 - APC express Nox2, they may affect T-cell responses via ROS mutated mice, reconstitution of macrophages (Mph) with ROS- production. Indeed, ROS produced during antigen presentation producing capacity was sufficient to protect the mice from affect the immune response (14, 15) by interfering in signal arthritis. Now, we present evidence that Mph-derived ROS induce transduction (16, 17). In addition, ROS generated in phagosomes/ Tregs. In vitro, we showed that Mph ROS-dependently induce endosomes determines the ability to cross-present antigen, both in Treg, using an NADPH-oxidase inhibitor. This finding was con- mice and humans (18, 19). We showed that among murine APCs, firmed genetically: rat or human CGD Mph with mutated p47phox fi phox macrophages (Mph) were most ef cient at producing ROS (20). or gp91 displayed hampered Treg induction and T-cell suppres- Transgenic mice expressing functional p47phox only in Mph on sion. However, basal Treg numbers in these subjects were compa- a p47phox-mutated background were as equally protected against rable to those in controls, indicating a role for ROS in induction of collagen-induced arthritis as their fully wild-type littermates. peripheral Tregs. Induction of allogeneic delayed-type hypersensi- These observations indicate that Mph-derived ROS are sufficient phox fi tivity with p47 -mutated Mph con rmed the importance of to inhibit T-cell responses (20). Mph-derived ROS in Treg induction in vivo. We conclude that Regulatory T cells (Tregs) can suppress activation and pro- NAPDH oxidase activity in Mph is important for the induction of liferation of effector T cells and thereby diminish immune re- fl Tregs to regulate T cell-mediated in ammation. sponses. Autoimmunity therefore can be the result of a defective Treg system (21), and successful treatment of autoimmune dis- chronic granulomatous disease | NADPH oxidase | neutrophil cytosolic ease with Tregs has been reported in mouse models (22, 23). We oxidase 1 | redox hypothesized that if Mph-derived ROS prevent T-cell–mediated immune responses, it could do so by inducing Tregs. Previously eactive oxygen species (ROS) not only are harmful and we showed that antiinflammatory Mph can induce potent Tregs, Rmediators of oxidative stress, but also have immune regula- in contrast to proinflammatory Mph (24). Here we investigated tory functions, especially when produced in lower amounts (1–3). whether Mph-derived ROS influence the induction of Tregs in The mechanisms by which ROS affect the immune system are humans in vitro as well as in rats in vivo. We observed that Mph just beginning to become clear. For example, mitochondrial ROS can induce Tregs in a ROS-dependent fashion in vitro and, more oxidize released high-mobility group protein B1 during apopto- importantly, that Mph from ROS-deficient CGD patients are sis, thereby preventing immune activation and allowing induction significantly less efficient in inducing Tregs. We conclude that Mph of tolerance (4), and myeloid-derived suppressor cells suppress can modulate T-cell responses by producing ROS and can induce antitumor T-cell responses in a phagocytic NADPH–oxidase Tregs in a ROS-dependent fashion. (Nox2) complex-dependent way (5). This Nox2 complex consists of multiple components (i.e., the membrane-expressed cyto- Results phox phox chrome b558 consisting of gp91 and p22 and the cytosolic Human Mph Produce ROS upon Stimulation. To investigate the role components p47phox, p67phox, and p40phox). Chronic granuloma- of ROS in antigen presentation by different APC, the expression phox tous disease (CGD) develops when any of these components is of two Nox2 members was determined: p47 (Ncf1) and phox absent or functionally hampered, and ROS production is de- gp91 (Cybb) in human dendritic cells (DC) and in Mph col- fective. CGD is characterized by recurrent bacterial and fungal infections and abnormal granuloma formation. These granulomas are mostly sterile and often respond to steroid therapy without Author contributions: M.D.K., N.D.L.S., C.v.K., and K.A.G. designed research; M.D.K., S.W.v.d.K., K.K., and K.A.G. performed research; J.W., J.M.v.d.B., and R.H. contributed antibiotics (6). In addition, CGD patients suffer from autoim- new reagents/analytic tools; N.D.L.S., J.W., T.H.M.O., T.W.K., C.v.K., and K.A.G. analyzed mune diseases more frequently than does the healthy population data; and M.D.K., N.D.L.S., T.H.M.O., T.W.K., R.H., C.v.K., and K.A.G. wrote the paper. (7, 8). These features point to a defect in immune regulation The authors declare no conflict of interest. caused by the absence of ROS. *This Direct Submission article had a prearranged editor. We observed previously that mice and rats with alleles of the 1 phox To whom correspondence may be addressed. E-mail: [email protected] or k.a.gelderman@ neutrophil cytosolic factor 1 (Ncf1) gene (encoding p47 ) that lumc.nl. encode a less functional Nox2 and thus have lower ROS pro- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. duction are more susceptible to induced autoimmune diseases 1073/pnas.1012016107/-/DCSupplemental. 17686–17691 | PNAS | October 12, 2010 | vol. 107 | no. 41 www.pnas.org/cgi/doi/10.1073/pnas.1012016107 Downloaded by guest on September 29, 2021 ony-stimulating factor (M-CSF)–differentiated Mph. mRNA served ROS-dependent suppression of T-cell activation by Mph expression for both p47phox and gp91phox was about 30 times could be mediated, at least in part, via induction of Tregs. To − higher in Mph than in DC (Fig. 1A). By intracellular FACS check this possibility, CD4+CD25 T cells were cocultured with analysis, we observed that the expression of gp91phox protein was Mph and anti-CD3/28 for 5 d, and the percentage of FoxP3+ cells very low in DC, whereas p47phox was clearly present. In contrast, among the CD3+CD4+CD25+ cells was assessed (Fig. 3 A, Left, Mph showed significant expression of both gp91phox and p47phox and B). The percentage of FoxP3+ cells among the CD3+ (Fig. 1B). Functionally, human Mph efficiently generated ROS CD4+CD25+ cells was increased upon coculture of T cells with upon phorbol 12-myristate 13-acetate (PMA) stimulation (Fig. 1 Mph, confirming their Treg-inducing capacity. Addition of apoc- C and D). In contrast, DC hardly produced ROS, in line with the ynin to these cultures significantly reduced the number of Tregs low gp91phox expression. Mph differentiated in GM-CSF (proin- (Fig. 3A, Right,andB), demonstrating the ROS dependency of Treg flammatory Mph) produced only marginal amounts of ROS (Fig induction. To determine the functional capacity of these Tregs, − S1A). The ROS production by Mph could be blocked to back- suppression assays were performed. CD4+CD25 T cells were ground levels with apocynin, an inhibitor of Nox2 that binds primed by Mph for 5 d in the presence of anti-CD3/28 and in the p47phox and prevents translocation to the membrane (Fig. 1E). absence or presence of apocynin. These primed T cells were used as − suppressor cells and combined with CD4+CD25 allogeneic car- Mph Suppress T-Cell Responses by Producing ROS. To investigate the boxyfluorescein succinimidyl ester (CFSE)-labeled responder suppressive capacity of ROS produced by APC on T-cell re- T cells and irradiated feeder cells. After 5 d, T-cell proliferation was sponses, purified T cells were activated with anti-CD3/CD28 assessed by 3H thymidine incorporation and CFSE dilution. T cells mAbs in the presence of increasing numbers of Mph or DC. IFN-γ primed with Mph suppressed the proliferation of responder T cells production and the proliferative response were determined at in a dose-dependent fashion. In line with the observed ROS de- day 5. IFN-γ production (Fig. 2 A and C and Fig. S1B) and, to pendence of FoxP3 induction, priming in presence of apocynin a lesser extent, T-cell proliferation (Fig.
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