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 na?ve 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) Determine the role of TLR7 and TLR9 in HIV-induced activation of IDO;(2) Elucidate the players in the noncanonical NFkB pathway for IDO expression;(3) .Examine the pDC-derived products that cause T reg generation. 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
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI089030-04
Application #
8444730
Study Section
Special Emphasis Panel (ZRG1-BBBP-J (29))
Program Officer
Adger-Johnson, Diane S
Project Start
2010-03-15
Project End
2015-03-14
Budget Start
2013-03-15
Budget End
2014-03-14
Support Year
4
Fiscal Year
2013
Total Cost
$42,232
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
Fernandez, Melissa V; Miller, Elizabeth A; Bhardwaj, Nina (2014) Activation and measurement of NLRP3 inflammasome activity using IL-1? in human monocyte-derived dendritic cells. J Vis Exp :