Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells
Bangxing Hong, … , Xue F. Huang, Si-Yi Chen
Bangxing Hong, … , Xue F. Huang, Si-Yi Chen
Published January 4, 2011
Citation Information: J Clin Invest. 2011;121(2):739-751. https://doi.org/10.1172/JCI42656.
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Research Article Virology

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

Abstract

Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20 — an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs — restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

Authors

Bangxing Hong, Xiao-Tong Song, Lisa Rollins, Lindsey Berry, Xue F. Huang, Si-Yi Chen

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Figure 2

Systemic immunization of Ad-siA20-BM-DCs induces mucosal anti-HIV immune response.

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Systemic immunization of Ad-siA20-BM-DCs induces mucosal anti-HIV immune...
Groups of mice were immunized twice with gp120-pulsed, Ad-transfected BM-DCs (1 × 106 cells/mouse) via footpad, followed by in vivo stimulation with poly(I:C). (A and B) Two weeks later, mesenteric LNs were harvested and pooled, and cell suspensions were then subjected to ICS. (C) The average cell numbers of IFN-γ/IL-2 double-positive CD8+ T cells and CD4+ T cells per mesenteric LN were examined. (D) The expression of effector molecules on gated CD8+ T cells from mesenteric LNs was also examined. (E) Mucosal HIV gp120–specific sIgA titers from the pooled sample of each group (4–6 mice/group) were quantified by capture ELISA. Antibody titers are reported as the mean ± SD of endpoint titers (36). Data from 1 experiment representative of 3 are presented. *P < 0.05, Ad-siGFP-BM-DCs versus Ad-siA20-BM-DCs.