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CD154 Activates Macrophage Antimicrobial Activity in the Absence of IFN- Γ Through a TNF- Α-Dependent Mechanism

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CD154 Activates Macrophage Antimicrobial Activity in the Absence of IFN- Γ Through a TNF- Α-Dependent Mechanism CD154 Activates Macrophage Antimicrobial Activity in the Absence of IFN- γ through a TNF- α-Dependent Mechanism This information is current as Rosa M. Andrade, Matthew Wessendarp and Carlos S. of September 27, 2021. Subauste J Immunol 2003; 171:6750-6756; ; doi: 10.4049/jimmunol.171.12.6750 http://www.jimmunol.org/content/171/12/6750 Downloaded from References This article cites 57 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/171/12/6750.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD154 Activates Macrophage Antimicrobial Activity in the Absence of IFN-␥ through a TNF-␣-Dependent Mechanism1 Rosa M. Andrade, Matthew Wessendarp, and Carlos S. Subauste2 Protection against certain intracellular pathogens can take place in the absence of IFN-␥ through mechanisms dependent on TNF-␣. In this regard, patients with partial defect in IFN-␥ receptor 1 are not susceptible to toxoplasmosis. Thus, we used a model of Toxoplasma gondii infection to investigate whether CD154 modulates IFN-␥-independent mechanisms of host protection. Hu- man monocyte-derived macrophages treated with recombinant CD154 exhibited increased anti-T. gondii activity. The number of tachyzoites per 100 macrophages at 20 h postinfection was lower in CD154-treated macrophages compared with controls. This was accompanied by a decrease in the percentage of infected cells in CD154-treated macrophages at 20 h compared with 1 h postin- fection. CD154-bearing cells also induced antimicrobial activity in T. gondii-infected macrophages. CD154 enhanced macrophage ␥ ␣ anti-T. gondii activity independently of IFN- . TNF- mediated the effects of CD154 on macrophage anti-T. gondii activity. CD154 Downloaded from increased TNF-␣ production by T. gondii-infected macrophages, and neutralization of TNF-␣ inhibited the effect of CD154 on macrophage anti-T. gondii activity. These results demonstrate that CD154 triggers TNF-␣-dependent antimicrobial activity in macrophages and suggest that CD154 regulates the mechanisms of host protection that take place when IFN-␥ signaling is deficient. The Journal of Immunology, 2003, 171: 6750–6756. ␥ ␥ nterferon- is considered a major mediator of host protection mediated by IFN- . However, the regulation of these mechanisms http://www.jimmunol.org/ against intracellular pathogens. However, there is increasing of host protection is not completely understood. I evidence pointing toward the presence of IFN-␥-independent CD154 is a member of the TNF family that plays a pivotal role mechanisms of control of these infections. In this regard, either in the regulation of cellular and humoral immunity. CD154 is ex- IFN-␥Ϫ/Ϫ or IFN-␥-receptorϪ/Ϫ (IFN-␥RϪ/Ϫ) mice exhibit pro- pressed as a membrane molecule (primarily on activated CD4ϩ T longed survival after infection with a virulent strain of Listeria cells) and as a soluble protein (8, 9). Through its interaction with monocytogenes if they are first infected with an attenuated strain or CD40, CD154 regulates many aspects of the immune response, are treated with anti-IL-4 mAb or TNF-␣ (1, 2). IFN-␥Ϫ/Ϫ mice including activation of APCs, priming of CD4ϩ and CD8ϩ T cells, infected with Leishmania donovani reduce parasite burden through stimulation of IL-12/IFN-␥ production, B cell proliferation, and Ig the action of endogenous TNF-␣ (3). Mice deficient in IFN regu- synthesis (10–12). The role of CD154 in orchestrating fundamen- by guest on September 27, 2021 latory factor-1 gene exhibit IFN-␥-independent mechanisms of re- tal aspects of the immune response is likely to explain why defec- sistance against Toxoplasma gondii (4). In addition, IFN-␥Ϫ/Ϫ tive CD154 signaling results in increased susceptibility to patho- mice control secondary infection with Histoplasma capsulatum via gens such as Leishmania, Pneumocystis carinii, T. gondii, a mechanism dependent on endogenous TNF-␣ (5). Together, Mycobacterium avium, Cryptosporidium parvum, Salmonella dub- these studies indicate that TNF-␣ may be central to the control of lin, and Candida albicans (13–20). intracellular pathogens in the absence of IFN-␥ (2, 3, 5). One of the consequences of CD154-mediated APC activation There is also indication that infections with certain intracellular appears to be enhancement of macrophage anti-microbial activity. pathogens can be controlled in humans with defective IFN-␥ sig- Studies in mice revealed that in the presence of IFN-␥, signaling naling. Although patients with congenital deficiencies in IFN-␥- through CD40 induces macrophage anti-Leishmania major and an- and IL-12-mediated immune response are susceptible to disease ti-T. gondii activities (14, 16). Studies in humans have reported caused by atypical Mycobacteria and Salmonella, diseases caused conflicting results about the effect of CD154 on macrophage anti- by other intracellular pathogens are uncommon (6). Indeed, pa- microbial activity. Although human monocyte-derived macrophages tients with partial IFN-␥R1 deficiency do not develop toxoplas- treated with CD154 impaired the intracellular growth of M. avium, mosis despite serological evidence of chronic infection with T. CD154 had no effect on the replication of Mycobacterium tuberculo- gondii (7). Thus, there is strong evidence for the existence of sis within these host cells (18, 21). Thus, it is not clear whether CD154 mechanisms of control of intracellular pathogens other than those can enhance macrophage antimicrobial activity in the absence of IFN-␥ and if this takes place in human macrophages. Using a model of T. gondii infection, we set out to determine whether CD154 modulates the antimicrobial activity of human Department of Internal Medicine, University of Cincinnati College of Medicine, Cin- macrophages in conditions where IFN-␥ is lacking or deficient. T. cinnati, OH 45267 gondii represents an excellent model for these studies because this Received for publication May 16, 2003. Accepted for publication October 2, 2003. pathogen is important in immunocompromised patients, macro- The costs of publication of this article were defrayed in part by the payment of page phage activation is crucial for host protection against T. gondii (22, charges. This article must therefore be hereby marked advertisement in accordance 23), and humans with defective IFN-␥ signaling are capable of with 18 U.S.C. Section 1734 solely to indicate this fact. controlling this pathogen (7). We report that CD154 activates hu- 1 This work was supported by National Institutes of Health Grant AI48406 (to C.S.S.). man macrophages to exhibit anti-T. gondii activity in both the 2 Address correspondence and reprint requests to Dr. Carlos S. Subauste, Department ␥ of Internal Medicine, University of Cincinnati College of Medicine, P.O. Box 670560, absence of IFN- and the presence of concentrations of this cyto- Cincinnati, OH 45267-0560. E-mail address: [email protected] kine insufficient to trigger full macrophage activation. In addition, Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 6751 we show that this effect of CD154 is mediated by TNF-␣. These ture, followed by addition of anti-CD40 FITC and anti-CD14-PE (Caltag, results suggest that CD154 regulates TNF-␣-dependent mecha- South San Francisco, CA) or isotype control mAbs. After 30-min incuba- nisms of host protection that operate when IFN-␥ signaling is tion on ice, cells were washed and fixed with 1% paraformaldehyde. The expression of CD40 was analyzed using a FACSCalibur (BD PharMingen). deficient. Addition of recombinant CD154 to macrophages before staining caused an 18% inhibition of the percentage of CD40ϩ cells. Materials and Methods Macrophage culture ELISA Macrophages were generated by culturing monocytes in complete medium Monolayers of monocyte-derived macrophages cultured in 96-well plates (CM)3 containing human serum. Briefly, PBMC were isolated after buffy were washed before infection. Supernatants were collected 4 h postinfec- coats of heparinized blood from healthy volunteers (Hoxworth Blood Cen- tion and were used to measure the concentration of TNF-␣ by ELISA ter, Cincinnati, OH) were centrifuged on Ficoll-Hypaque gradients (Am- (Endogen, Cambridge, MA). The lower limit of detection of the assay was ersham Pharmacia Biotech, Piscataway, NJ). Monocytes were purified by 9 pg/ml. Supernatants from monolayers were collected at the end of the 5-d incubating PBMC with the following mAbs (all from BD PharMingen (San culture and used to measure IFN-␥ levels by ELISA (Endogen). The lower Jose, CA), except when indicated): anti-CD2, anti-CD3, anti-CD8, anti- limit of detection of the assay was
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