T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages
Ryan M Walk,1,2 Steven T Elliott,2 Felix C Blanco,2 Jason A Snyder,2 Ashley M Jacobi,3 Scott D Rose,3 Mark A Behlke,3 Aliasger K Salem,4 Stanislav Vukmanovic,2 Anthony D Sandler21Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2Sheikh Zayed Institute for Pediatric Surgic...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2012-11-01
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| Series: | ImmunoTargets and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/t-cell-activation-is-enhanced-by-targeting-il-10-cytokine-production-i-peer-reviewed-article-ITT |
| _version_ | 1818968445814833152 |
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| author | Walk RM Elliot ST Blanco FC Snyder JA Jacobi AM Rose SD Behlke MA Salem AK Vukmanovic S Sandler AD |
| author_facet | Walk RM Elliot ST Blanco FC Snyder JA Jacobi AM Rose SD Behlke MA Salem AK Vukmanovic S Sandler AD |
| author_sort | Walk RM |
| collection | DOAJ |
| description | Ryan M Walk,1,2 Steven T Elliott,2 Felix C Blanco,2 Jason A Snyder,2 Ashley M Jacobi,3 Scott D Rose,3 Mark A Behlke,3 Aliasger K Salem,4 Stanislav Vukmanovic,2 Anthony D Sandler21Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC, USA; 3Integrated DNA Technologies, Coralville, IA, USA; 4Division of Pharmaceutics, University of Iowa, Iowa City, IA, USAAbstract: Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-α. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10.Keywords: toll-like receptors, innate immunity, IL-10 |
| first_indexed | 2024-12-20T14:04:49Z |
| format | Article |
| id | doaj.art-28f718d2f1e1486cb1bf5f3d25a9f27d |
| institution | Directory Open Access Journal |
| issn | 2253-1556 |
| language | English |
| last_indexed | 2024-12-20T14:04:49Z |
| publishDate | 2012-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | ImmunoTargets and Therapy |
| spelling | doaj.art-28f718d2f1e1486cb1bf5f3d25a9f27d2022-12-21T19:38:16ZengDove Medical PressImmunoTargets and Therapy2253-15562012-11-012012Issue 1132311596T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophagesWalk RMElliot STBlanco FCSnyder JAJacobi AMRose SDBehlke MASalem AKVukmanovic SSandler ADRyan M Walk,1,2 Steven T Elliott,2 Felix C Blanco,2 Jason A Snyder,2 Ashley M Jacobi,3 Scott D Rose,3 Mark A Behlke,3 Aliasger K Salem,4 Stanislav Vukmanovic,2 Anthony D Sandler21Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC, USA; 3Integrated DNA Technologies, Coralville, IA, USA; 4Division of Pharmaceutics, University of Iowa, Iowa City, IA, USAAbstract: Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-α. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10.Keywords: toll-like receptors, innate immunity, IL-10https://www.dovepress.com/t-cell-activation-is-enhanced-by-targeting-il-10-cytokine-production-i-peer-reviewed-article-ITTToll like receptorsinnate immunityIL-10 |
| spellingShingle | Walk RM Elliot ST Blanco FC Snyder JA Jacobi AM Rose SD Behlke MA Salem AK Vukmanovic S Sandler AD T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages ImmunoTargets and Therapy Toll like receptors innate immunity IL-10 |
| title | T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages |
| title_full | T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages |
| title_fullStr | T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages |
| title_full_unstemmed | T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages |
| title_short | T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages |
| title_sort | t cell activation is enhanced by targeting il 10 cytokine production in toll like receptor stimulated macrophages |
| topic | Toll like receptors innate immunity IL-10 |
| url | https://www.dovepress.com/t-cell-activation-is-enhanced-by-targeting-il-10-cytokine-production-i-peer-reviewed-article-ITT |
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