Human plasmacytoid dendritic cells (pDC) constitute a rare subset of blood dendritic cells (DC), distinct from myeloid CD11c+, """"""""conventional"""""""" DC (cDC). Through production of high levels of type I IFN in response to virus infection, pDC serve as a critical link between innate and adaptive antiviral immune responses. Recent observations from my laboratory have highlighted their particular role in the immune regulation of HIV-1 infection. pDCs, but not cDCs, undergo activation following CD4 mediated endocytosis of HIV-1 and subsequent activation of TLR7 with genomic RNA. Activated pDCs upregulate costimulatory molecules, produce pro-inflammatory cytokines and chemokines and activate immature cDCs in a bystander fashion. As a counterpoint to the induction of these anti-viral responses, HIV-activated pDCs simultaneously induce the differentiation of Tregulatory cells (Tregs) from naive resting CD4+ T cells, in a TLR7 dependent manner. Treg generation requires the expression of indolamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan to kynurenine, as it is reversed upon addition of the specific inhibitor 1 methyl-tryptophan. The T regs generated (""""""""inducible T regs"""""""") inhibit the proliferation of activated T cells and maturation of cDC, thereby attenuating the induction of ongoing adaptive immune responses. Thus pDCs inhibit viral replication and promote anti-viral immunity, but at the same time limit the extent of immune activation. This newly ascribed property of pDCs is especially relevant in HIV infection where control of excessive immune activation could be essential to prevent virus dissemination and progression of disease. In this application we propose to: (1) Identify the mechanism(s) underlying HIV-dependent, pDC-induced T reg differentiation, focusing in particular on IDO;(2) Determine the regulatory processes used by Tregs to inhibit T cell growth and cDC activation;(3) Establish the in vivo relevance of pDC-mediated induction of Treg in HIV-infected patients. These studies will greatly improve our understanding of the events that follow pDC activation by HIV and potentially result in clinically applicable approaches to enhance anti-HIV immune responses in vivo.

Public Health Relevance

These studies will investigate the mechanisms used by the HIV virus to evade the immune system. Specifically, we will explore how HIV induces the generation of T cells which have suppressive qualities and block the development of several beneficial anti-viral responses. By understanding how these suppressive T cells are generated we can devise strategies to modulate their function and promote anti-viral immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081848-02
Application #
8058751
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Lapham, Cheryl K
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$418,275
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Solovyov, Alexander; Vabret, Nicolas; Arora, Kshitij S et al. (2018) Global Cancer Transcriptome Quantifies Repeat Element Polarization between Immunotherapy Responsive and T Cell Suppressive Classes. Cell Rep 23:512-521
Balan, Sreekumar; Arnold-Schrauf, Catharina; Abbas, Abdenour et al. (2018) Large-Scale Human Dendritic Cell Differentiation Revealing Notch-Dependent Lineage Bifurcation and Heterogeneity. Cell Rep 24:1902-1915.e6
Saxena, Mansi; Balan, Sreekumar; Roudko, Vladimir et al. (2018) Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng 2:341-346
Saxena, Mansi; Bhardwaj, Nina (2018) Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment. Trends Cancer 4:119-137
Kyi, Chrisann; Roudko, Vladimir; Sabado, Rachel et al. (2018) Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial. Clin Cancer Res 24:4937-4948
Balan, Sreekumar; Finnigan, John; Bhardwaj, Nina (2017) Dendritic Cell Strategies for Eliciting Mutation-Derived Tumor Antigen Responses in Patients. Cancer J 23:131-137
Sabado, Rachel L; Balan, Sreekumar; Bhardwaj, Nina (2017) Dendritic cell-based immunotherapy. Cell Res 27:74-95
Saxena, Mansi; Bhardwaj, Nina (2017) Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr Opin Immunol 47:35-43
Fernandez, Melissa Victoria; Miller, Elizabeth; Krammer, Florian et al. (2016) Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells. J Leukoc Biol 99:723-34
O'Brien, Meagan; Manches, Olivier; Wilen, Craig et al. (2016) CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells. PLoS Pathog 12:e1005553

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