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.
View: Text | PDF
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

×

Figure 7

Ad-siA20-BM-DCs had a reduced ability to activate Foxp3+ Tregs.

Options: View larger image (or click on image) Download as PowerPoint
Ad-siA20-BM-DCs had a reduced ability to activate Foxp3+ Tregs. (A) ...
(A) Enhanced expression of IL-12 and IL-27 by Ad-siA20-BM-DCs after 24 hours of stimulation with LPS in vitro. *P < 0.05, **P < 0.01, Ad-siGFP-BM-DCs versus Ad-siA20-BM-DCs. (B) Enhanced activation of antigen-specific CD8+ T cells by Ad-siA20-BM-DCs in vitro. CD8+ OT-I T cells (5 × 105 cells) from OT-I transgenic mice were cocultured with Ad-siA20-BM-DCs or Ad-siGFP-BM-DCs (1 × 105 cells) pulsed with 5 μg/ml of OT-I peptide for 5 days. [3H]thymidine incorporation rates and cytokine production of OT-I cells after the depletion of CD11c+ DCs were then examined. Data from 1 representative experiment of 3 are presented. *P < 0.05, Ad-siGFP-BM-DCs versus Ad-siA20-BM-DCs. (C and D) Enhanced activation of antigen-specific CD4+ Th cells. CD4+ OT-II T cells from OT-II transgenic mice were cocultured with Ad-siA20-BM-DCs or Ad-siGFP-BM-DCs (1 × 105 cells) pulsed with 5 μg/ml OT-II peptide for 5 days. [3H]thymidine incorporation rates and Th1- and Th2-polarizing cytokine production (C) and intracellular IL-17 or Foxp3 expression (D) of OT-II cells after the depletion of CD11c+ DCs were then examined; data from 1 representative experiment of 3 are presented. *P < 0.05, Ad-siGFP-BM-DCs versus Ad-siA20-BM-DCs.