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

Abstract

HIV modulates plasmacytoid dendritic cell (pDC) activation via Tolllike 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 receptorassociated 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.

Dendritic Cell Maturation and Survival Are Differentially Regulated by TNFR1 and TNFR2

“…Alternatively, development of a therapeutic TNFR2 agonist may be a useful and convenient tool for the ex vivo generation of tolerogenic DC-based immunotherapies, as it may prolong the survival of these tolerogenic DC without inducing their maturation. Additionally, and in contrast to above the noncanonical NFkB pathway, RelB:p52 has been implicated in the control of the immunoregulatory phenotype of DC (57)(58)(59). Because TNFR2 activates primarily the noncanonical p52 NF-kB pathway, it is tempting to speculate that TNFR2 is involved in the induction/ maintenance of self-tolerance by inducing tolerogenic DC.…”

IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis

“…Thus, pDC are an important source of IDO1 expression activated by IFN-a, and this has also been observed in humans treated with IFN-a (25). An anti-inflammatory effect of IDO1-expressing pDC has earlier been anticipated in a number of experimental studies, including prevention of atherosclerosis (26), regulation of HIV responses (27,28), and amelioration of experimental encephalitis (29), to name a few. In line with such observations, we showed in this work that pDC were critically involved in IFN-a-mediated protection against AIA (Fig.…”

“…Binding of CTLA-4 to CD80/86 (B7) on DC regulates IDO1-mediated Trp catabolism in DC and thereby their immunosuppressive capacity (28,41). In fact, CTLA-4-mediated activation of IDO1 may be a natural way to prevent development of rheumatoid arthritis (RA) because point mutations in the CTLA-4 gene in RA patients result in lower IDO1 enzymatic activity, which may explain the decreased serum levels of Kyn in a cohort of RA patients (42).…”

HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx

“…pDCs also contribute to chronic inflammation in HIV-1 infection by producing proinflammatory cytokines and chemokines [6][7][8] and may suppress the immune response by producing indoleamine (2,3)-dioxygenase (IDO) 9,10 which induces Treg differentiation. pDCs likely play a role in the early stages of infection by recruiting CCR5 + CD4 + T cells to mucosal sites of transmission 11 and by inducing the activation and apoptosis of CD4 + T cells through the production of type-I IFN.…”