The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Abstract

Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Myeloid-associated lymphotoxin-beta receptor (LTbetaR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses on the LTbetaR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTbetaR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets.

Figure 1

Immediate TNF/LT Family-Integrated signaling. Both homotrimeric TNF and soluble LTα₃ interact with TNFR1 and TNFR2. LTβR binds two ligands, the membrane LTα₁β₂ and LIGHT, yet LIGHT can also engage the herpes virus entry mediator. HVEM interacts with BTLA, a member of the Ig superfamily. The arrowed lines indicate the binding interactions among the members. Decoy receptor-3 (DcR3) is secreted and binds LIGHT (also Fas Ligand and TL1A, not shown).

Figure 2

Schematic model representing the regulation of DC homeostasis by a LTαβ and HVEM-BTLA-integrated circuit. The specific details of the model are described in the text.

Figure 3

TNFR and LTβR signaling pathways for NFκB activation. Signaling through TNFR activates the canonical RelA NFκB pathway, which involves the α, β and γ (NEMO) subunits of the IκB kinase (IKK) complex, which leads to proteosomal degradation of IκB, releasing RelA/p50 dimer from its cytoplasmic constraint, locate to the nucleus and binding κB transcriptional target sequences. LTβR ligation activates the serine kinases NIK and IKKα (also a part of the canonical pathway). The phosphorylation and ubiquitin-dependent proteasomal degradation of p100 results in the processing of the precursor to the p52 subunit and accumulation of p52-RelB heterodimers to the nucleus. Signaling through the LTβR also leads to the activation of the classical NF-κB pathway. TNFR signaling rapidly activates a large number of proinflammatory genes, whereas LTβR activation of RelB takes several hours but sustained expression in the nucleus leads to different sets of activated genes involved in homeostasis, such as the chemokine, CCL21.