ILC3s control splenic cDC homeostasis via lymphotoxin signaling.

The spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα1β2-expressing Rorgt+ ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα+CD4+Esam+ cDC2s, independently of the microbiota and of bone marrow pre-cDC output.

Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs.

A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator.

The human cytomegalovirus opening reading frame UL144 is an ortholog of the TNF receptor superfamily member, herpesvirus entry mediator (HVEM; ). HVEM binds the TNF ligands, LIGHT and LTa; the immunoglobulin inhibitory receptor, B and T lymphocyte attenuator (BTLA); and the natural killer cell-activating receptor CD160. However, UL144 selectively binds BTLA, avoiding activation of inflammatory signaling initiated by CD160 in natural killer cells.

LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.

Objectives: The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer.

Commensal microbiota influence systemic autoimmune responses.

Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance against nuclear self-constituents remain largely unresolved. Using mice deficient in lymphotoxin and Hox11, we report that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies.

Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-αβ and are elevated in rheumatoid arthritis.

Innate lymphoid cells encompass a diverse array of lymphocyte subsets with unique phenotype that initiate inflammation and provide host defenses in specific microenvironments. In this study, we identify a rare human CD4(+)CD3(-) innate-like lymphoid population with high TNF expression that is enriched in blood from patients with rheumatoid arthritis. These CD4(+)CD3(-) cells belong to the T cell lineage, but the lack of AgR at the cell surface renders them nonresponsive to TCR-directed stimuli.

CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells.

Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage herpesvirus entry mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells.

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling.

Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia.

Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability.

The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LTbetaR) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown.

Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor.

The lymphotoxin-beta receptor (LTbetaR) activates the NF-kappaB2 transcription factors, p100 and RelB, by regulating the NF-kappaB-inducing kinase (NIK). Constitutive proteosomal degradation of NIK limits NF-kappaB activation in unstimulated cells by the ubiquitin:NIK E3 ligase comprised of subunits TNFR-associated factors (TRAF)3, TRAF2, and cellular inhibitor of apoptosis (cIAP). However, the mechanism releasing NIK from constitutive degradation remains unclear.

T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.

The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-kappaB RelA transcriptional complex raising the question of how NF-kappaB activation is repressed in naive T cells.

Unconventional ligand activation of herpesvirus entry mediator signals cell survival.

The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-kappaB through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells. Emerging evidence indicates BTLA also promotes T cell survival, but its structural differences from LIGHT intimate BTLA is unlikely to function as an activator of HVEM.

Structural determinants of herpesvirus entry mediator recognition by murine B and T lymphocyte attenuator.

The B and T lymphocyte attenuator (BTLA) appears to act as a negative regulator of T cell activation and growth. BTLA specifically interacts with herpesvirus entry mediator (HVEM), a member of the TNFR family. Herein, we have undertaken surface plasmon resonance studies to quantitatively assess BTLA and HVEM ectodomain interactions.

The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells.

Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-beta receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LTalpha, LTbeta, LTbetaR, and the NFkappaB inducing kinase show a specific loss of CD8- DC subsets. In contrast, the CD8alpha- DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA).

The LT beta R signaling pathway.

The lymphotoxin-beta receptor (LTbetaR, TNFRSF3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. The TNF receptor associated factors (TRAF)-2, 3 and 5 function as adaptors linking LTbetaR signaling targets. Interestingly, TRAF deficient mice do not phenocopy mice deficient in components of the LTbetaR pathway, presenting a conundrum.

Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta.

NK cells play a key role in host defense against the beta-herpesvirus CMV through perforin-dependent cytolysis. In this study, we show that human NK cells can also control human CMV (HCMV) infection by a noncytolytic mechanism involving induction of IFN-beta in the virus-infected cell. Both IL-2-activated primary NK cells and an IL-2-dependent NK cell line (NK-92) exhibited potent, noncytolytic anti-HCMV activity at very low E:T cell ratios (<0.

Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway.

The herpesvirus entry mediator (HVEM), a member of the TNF receptor (TNFR) superfamily, can act as a molecular switch that modulates T cell activation by propagating positive signals from the TNF-related ligand LIGHT (TNFR superfamily 14), or inhibitory signals through the Ig superfamily member B and T lymphocyte attenuator (BTLA). Competitive binding analysis and mutagenesis reveals a unique BTLA binding site centered on a critical lysine residue in cysteine-rich domain 1 of HVEM. The BTLA binding site on HVEM overlaps with the binding site for the herpes simplex virus 1 envelope glycoprotein D, but is distinct from where LIGHT binds, yet glycoprotein D inhibits the binding of both ligands, potentially nullifying the pathway.

Structurally distinct recognition motifs in lymphotoxin-beta receptor and CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling.

Lymphotoxin-beta receptor (LTbetaR) and CD40 are members of the tumor necrosis factor family of signaling receptors that regulate cell survival or death through activation of NF-kappaB. These receptors transmit signals through downstream adaptor proteins called tumor necrosis factor receptor-associated factors (TRAFs). In this study, the crystal structure of a region of the cytoplasmic domain of LTbetaR bound to TRAF3 has revealed an unexpected new recognition motif, 388IPEEGD393, for TRAF3 binding.

To kill or be killed: viral evasion of apoptosis.

In the struggle between virus and host, control over the cell's death machinery is crucial for survival. Viruses are obligatory intracellular parasites and, as such, must modulate apoptotic pathways to control the lifespan of their host in order to complete their replication cycle. Many of the counter-assaults mounted by the immune system incorporate activation of the apoptotic pathway-particularly by members of the tumor necrosis factor cytokine family-as a mechanism to restrict viral replication.