Homeostatic NF-κB Signaling in Steady-State Migratory Dendritic Cells Regulates Immune Homeostasis and Tolerance

Abstract

Migratory non-lymphoid tissue dendritic cells (NLT-DCs) transport antigens to lymph nodes (LNs) and are required for protective immune responses in the context of inflammation and to promote tolerance to self-antigens in steady-state. However, the molecular mechanisms that elicit steady-state NLT-DC maturation and migration are unknown. By comparing the transcriptome of NLT-DCs in the skin with their migratory counterparts in draining LNs, we have identified a novel NF-κB-regulated gene network specific to migratory DCs. We show that targeted deletion of IKKβ in DCs, a major activator of NF-κB, prevents NLT-DC accumulation in LNs and compromises regulatory T cell conversion in vivo. This was associated with impaired tolerance and autoimmunity. NF-κB is generally considered the prototypical pro-inflammatory transcription factor, but this study describes a role for NF-κB signaling in DCs for immune homeostasis and tolerance that could have implications in autoimmune diseases and immunity.

Concurrent CCR7 Overexpression and RelB Knockdown in Immature Dendritic Cells Induces Immune Tolerance and Improves Skin-Graft Survival in a Murine Model

“…It was also reported CCR7 blockade led to improved graft survival in lowrisk corneal transplantation [10]. On the other hand, RelB is required for the steady-state accumulation of migratory DCs in draining LNs, and a deficiency of the alternative RelB/p52 signaling pathway was shown to decrease DC migration ability [19]. However, in the present study, we found that even the imDCs with CCR7 overexpression maintain the immature status after LPS stimulation because of the low RelB expression.…”

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

“…Mice with targeted deletion of inhibitory kB kinase in DCs were recently reported to have a similarly strong defect in their accumulation of migratory DCs in cutaneous LN, leading to impaired generation of Treg cells in these LN and spontaneous development of autoimmunity (52). Deleting MyD88 specifically in CD11c + cells, however, resulted in only modest alterations in T cell responses in MLN after oral administration of Ag in the absence of adjuvant.…”

Duality at the gate: Skin dendritic cells as mediators of vaccine immunity and tolerance

“…DC specific loss of NF-kB signaling in mice resulted in loss of tolerance to self antigens in the steadystate, resulting in a lupus-like autoimmune phenotype marked by significantly increased lymph node size, as well as increased germinal centers and antinuclear antibody deposits in the kidney. 41 In addition to these studies, one study using gene gun based vaccination also noted higher numbers of CD4…”

“…This migration is CCR7 dependent, as mice genetically deficient for CCR7 mice do not have any migDCs in their cutaneous LNs. 17 Unexpectedly, skin DC constitutively migrate in both germ free and MyD88/TRIF knockout mice, 40 but fail to migrate when NF-kB signaling is inhibited in DCs, 41 suggesting that the migratory program occurs independently of TLR signaling, but requires NF-kB. However, irritant induced inflammation, 42 TLR ligation, 43 and infection 44 result in increased trafficking, demonstrating that skin DC migration is responsive to immune stimuli.…”

“…Another recent study has also identified a number of these tolerance associated genes when comparing migratory DC in the skin to those in the lymph node, suggesting that at least a large part of the program we identified may be amplified following migration to the cutaneous lymph node. 41 Collectively, overlapping features of the tolerance signature and migration signature are programmed through NFkB signaling in DCs. DC specific loss of NF-kB signaling in mice resulted in loss of tolerance to self antigens in the steadystate, resulting in a lupus-like autoimmune phenotype marked by significantly increased lymph node size, as well as increased germinal centers and antinuclear antibody deposits in the kidney.…”