Abstract
HIV modulates plasmacytoid dendritic cell (pDC) activation via Toll-like receptor 7, inducing type I IFN and inflammatory cytokines. Simultaneously, pDCs up-regulate the expression of indoleamine 2,3 dioxygenase (IDO), which is essential for the induction of regulatory T cells (Tregs), which function to down-modulate immune activation. Here we demonstrate the crucial importance of the noncanonical NF-κB pathway in the establishment of this immunoregulatory phenotype in pDCs. In response to HIV, the noncanonical NF-κB pathway directly induces IDO and involves the recruitment of TNF receptor-associated factor-3 to the Toll-like receptor/MyD88 complex, NF-κB-inducing kinase-dependent IκB kinase-α activation, and p52/RelB nuclear translocation. We also show that pDC-induced Tregs can inhibit conventional DC (cDC) maturation partially through cytotoxic T-lymphocyte antigen (CTLA)-4 engagement. Furthermore, CTLA-4 induces IDO in cDCs in a NF-κB-inducing kinase-dependent way. These CTLA-4-conditioned cDCs can in turn induce Treg differentiation in an IDO-dependent manner. Thus, the noncanonical NF-κB pathway is integral in controlling immunoregulatory phenotypes of both pDCs and cDCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Dendritic Cells / immunology*
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Dendritic Cells / virology*
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Gene Expression / immunology
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Gene Knockdown Techniques
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HIV Infections / immunology*
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HIV Infections / metabolism
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / immunology
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I-kappa B Kinase / metabolism
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Immunophenotyping
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Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
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Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B p52 Subunit / immunology*
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NF-kappa B p52 Subunit / metabolism
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NF-kappaB-Inducing Kinase
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / immunology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / virology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / virology*
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TNF Receptor-Associated Factor 3 / immunology
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TNF Receptor-Associated Factor 3 / metabolism
Substances
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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NF-kappa B p52 Subunit
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TNF Receptor-Associated Factor 3
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TRAF3 protein, human
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Protein Serine-Threonine Kinases
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I-kappa B Kinase