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 1

Ad-siA20-BM-DCs induce potent systemic HIV gp120–specific immune responses.

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Ad-siA20-BM-DCs induce potent systemic HIV gp120–specific immune respons...
Groups of C57BL/6 mice were immunized with HIV gp120 protein–pulsed (100 μg/ml), Ad-transfected BM-DCs (1 × 106 cells/mouse) twice with a week interval, followed by no stimulation or poly(I:C) (50 μg/mouse) or LPS stimulation (30 μg/mouse) (i.p.) daily for 3 consecutive days after each DC immunization. (A) CD8+ T cells or CD4+ T cells isolated from pooled splenocytes of immunized mice (n = 2–3) were subjected to IFN-γ ELISPOT assays. (B and C) ICS of CD8+ T cells (B) and CD4+ T cells (C) from draining LNs of immunized mice was performed after 6–8 hours in vitro restimulation. (D) The expression levels of perforin, granzymes A and B, and FasL in gated CD8+ T cells of pooled draining LNs of immunized mice are shown. (E) Systemic antibody responses enhanced by siA20-BM-DCs. HIV gp120–specific IgG1 and IgG2a subclass 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). Experiments were repeated 3 times with similar results. *P < 0.05, **P < 0.01, Ad-siGFP-BM-DCs versus Ad-siA20-BM-DCs.