T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor- stimulated macrophages

• Main Authors: Walk RM, Elliot ST, Blanco FC, Snyder JA, Jacobi AM, Rose SD, Behlke MA, Salem AK, Vukmanovic S, Sandler AD
• Format: Article
• Language: English
• Published: Dove Medical Press 2012-11-01
• Series: ImmunoTargets and Therapy
• Subjects: Toll like receptors; innate immunity; IL-10
• Online Access: https://www.dovepress.com/t-cell-activation-is-enhanced-by-targeting-il-10-cytokine-production-i-peer-reviewed-article-ITT

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