Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Olivier Manches, Melissa Victoria Fernandez, Joel Plumas, Laurence Chaperot, Nina Bhardwaj

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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.

Original languageEnglish
Pages (from-to)14122-14127
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number35
DOIs
StatePublished - 28 Aug 2012
Externally publishedYes

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