title: Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype.
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.
authors.affiliation: Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Manches
authors.forename: Melissa Victoria
authors.initials: MV
authors.lastname: Fernandez
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D015870:Gene Expression / Q000276:immunology; D055785:Gene Knockdown Techniques; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000276:immunology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology*; D048008:TNF Receptor-Associated Factor 3 / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053594:Myeloid Differentiation Factor 88; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C507779:MYD88 protein, human; C090656:TRAF3 protein, human