Activation of the noncanonical NF-?B 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-?B pathway in the establishment of this immunoregulatory phenotype in pDCs. In response to HIV, the noncanonical NF-?B pathway directly induces IDO and involves the recruitment of TNF receptor-associated factor-3 to the Toll-like receptor/MyD88 complex, NF-?B-inducing kinase-dependent I?B kinase-? 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-?B-inducing kinase-dependent way. These CTLA-4-conditioned cDCs can in turn induce Treg differentiation in an IDO-dependent manner. Thus, the noncanonical NF-?B pathway is integral in controlling immunoregulatory phenotypes of both pDCs and cDCs.

SUBMITTER: Manches O 

PROVIDER: S-EPMC3435221 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other