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Enhanced induction of HIV-specific Cytotoxic T Lymphocytes by Dendritic cell-targeted delivery of SOCS-1 siRNA

Subramanya, Sandesh, Armant, Myriam, Salkowitz, Janelle R., Nyakeriga, Alice M., Haridas, Viraga, Hasan, Maroof, Bansal, Anju, Goepfert, Paul A., Wynn, Katherine, Ladell, Kristin Ingrid, Price, David, N, Manjunath, Kan-Mitchell, June and Shankar, Premlata 2010. Enhanced induction of HIV-specific Cytotoxic T Lymphocytes by Dendritic cell-targeted delivery of SOCS-1 siRNA. Molecular Therapy 18 (11) , pp. 2028-2037. 10.1038/mt.2010.148

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Abstract

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the activation of T cells. RNA interference (RNAi)-mediated silencing of negative immunoregulatory molecules expressed by DCs may provide a strategy to enhance the potency of DC-based vaccines and immunotherapy. Ablation of suppressor of cytokine signaling-1 (SOCS-1) in antigen-presenting cells has been shown to enhance cellular immune response in mice. Here, we used a previously reported DC-targeting approach to deliver small interfering RNA (siRNA) against SOCS-1 to human myeloid-derived DCs (MDDCs). SOCS1-silencing in MDDCs resulted in enhanced cytokine responses to lipopolysaccharide (LPS) and a strong mixed-lymphocyte reaction. Moreover, only DCs treated with SOCS-1 siRNA, and not controls, elicited strong primary in vitro responses to well-characterized HLA-A*0201-restricted Melan-A/MART-1 and human immunodeficiency virus (HIV) Gag epitopes in naive CD8+ T cells from healthy donors. Finally, stimulation of CD8+ T cells from HIV-seropositive subjects with SOCS1-silenced DCs resulted in an augmented polyfunctional cytotoxic T-lymphocyte (CTL) response, suggesting that SOCS-1 silencing can restore functionally compromised T cells in HIV infection. Collectively, these results demonstrate the feasibility of DC3-9dR-mediated manipulation of DC function to enhance DC immunogenicity for potential vaccine or immunotherapeutic applications.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RZ Other systems of medicine
Publisher: Elsevier
ISSN: 1525-0016
Last Modified: 04 Jun 2017 03:59
URI: http://orca.cf.ac.uk/id/eprint/30230

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