An Alternative Pathway of NF-κB Activation Results in Maturation and T Cell Priming Activity of Dendritic Cells Overexpressing a Mutated IκBα

Abstract

Maturation of dendritic cells (DC) is a critical step in the induction of T cell responses and depends on the activation of NF-κB transcription factors. Therefore, inhibition of NF-κB activation has been proposed as a strategy to maintain DC in an immature stage and to promote immune tolerance. Herein, we generated murine myeloid DC expressing a mutated IκBα acting as a superrepressor of the classical NF-κB pathway (s-rIκB DC) to investigate the consequences of NF-κB inhibition on the ability of DC to prime T cell responses. Upon in vitro LPS activation, maturation of s-rIκB DC was profoundly impaired as indicated by defective up-regulation of MHC class II and costimulatory molecules and reduced secretion of IL-12 p70 and TNF-α. In contrast, after injection, s-rIκB DC had the same capacity as control DC to migrate to draining lymph node and to induce Th1- and Th2-type cytokine production in a MHC class II-incompatible host mice. Likewise, s-rIκB DC pulsed with OVA were as efficient as control DC to induce Ag-specific T cell responses in vivo. Indeed, further in vitro experiments established that s-rIκB DC undergo efficient maturation upon prolonged contact with activated T cells via the alternative pathway of NF-κB activation triggered at least partly by lymphotoxin β receptor ligation and involving processing of p100/RelB complexes.

Antigen-Specific Suppression of Inflammatory Arthritis Using Liposomes

“…This is because neither Bay11-7082 alone, curcumin liposomes containing irrelevant Ag, nor curcumin liposomes and soluble arthritogenic Ag administered concurrently were sufficient to induce FoxP3 ϩ Treg cells or to suppress arthritis. Rather, we and others have shown that blocking RelB activity inhibits functional DC differentiation, with induction of Treg specific for delivered Ag (7,28,29).…”

TRAF3 Controls Activation of the Canonical and Alternative NFκB by the Lymphotoxin Beta Receptor

“…The immunogenic capacity of DCs is controlled by their maturation stage: immature or semi-mature DCs induce anergy or tolerance, while only fully mature DCs are able to prime T cells (46,47). Maturation and immunogenic activity of dendritic cells require either TLR stimulation by pathogens or the activation of alternative NFB pathway by antigen-stimulated lymphocytes (48,49). The ability of either LTBR or CD40 to efficiently induce DC maturation and immunogenic activity (49,50) suggests the involvement of a shared component, such as TRAF3, in the activation of the alternative NFB pathway by these receptors.…”

“…30). On the other hand, the repression of classical NFB pathway in dendritic cells, while interfering with their innate immune functions and their activation by various TLR ligands, is unable to inhibit T-cell induced maturation through the alternative NFB pathway (48). The requirement for either TLR or lymphocyte induced signals for the full maturation of DCs is consistent with the ability of tissue-resident as well as semi-mature migratory DCs to generally ignore self-antigens or commensal flora and prevent priming of bystander lymphocytes (46).…”

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

“…After 6 days, non-adherent cells corresponding to DC-enriched fraction routinely contained more than 95% of DC as assessed by fluorescence-activated cell-sorter analysis. Murine BMDC were generated from bone marrows of WT or knock-out C57BL/6 mice in GM-CSF-containing medium according the protocol described by Moore et al [51] with slight modifications. The cells were fed with every 3 days of culture with recombinant murine GM-CSF and were used for assays at day 14 of culture.…”