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The operation of both central and peripheral tolerance ensures the prevention of autoimmune diseases. The maintenance of peripheral tolerance requires self-antigen presentation by professional antigen presenting cells (APCs). Dendritic cells (DCs) are considered as major APCs involved in this process. The current review discusses the role of DCs in autoimmune diseases, the various factors involved in the induction and maintenance of tolerogenic DC phenotype, and pinpoints their therapeutic capacity as well as potential novel targets for future clinical studies.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

One strategy to address the variable effectiveness of many influenza vaccines is to induce antiviral resident memory T cells, which can mediate cross-protection against multiple substrains (heterosubtypic immunity). Unfortunately, such vaccines typically use attenuated active viruses, which may be unsafe for certain populations. Wang et al. report a vaccine using an inactivated virus that effectively induced heterosubtypic immunity in both mice and ferrets (see the Perspective by Herold and Sander). They coadministered the virus with 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), a potent activator of the innate immune system, encapsulated in pulmonary surfactant–biomimetic liposomes. This adjuvant was taken up by alveolar epithelial cells, whose activation resulted in effective antiviral T cell and humoral immune responses without accompanying immunopathology. Science , this issue p. eaau0810 ; see also p. 852 Biomimetic liposomes containing an innate immune adjuvant promote effective immunity using an inactivated influenza vaccine. Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)–biomimetic liposomes encapsulating 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine–induced humoral and CD8 + T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP–adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8 + T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP–mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.

Chirality is a unifying structural metric of biological and abiological forms of matter. Over the past decade, considerable clarity has been achieved in understanding the chemistry and physics of chiral inorganic nanoparticles 1 – 4 ; however, little is known about their effects on complex biochemical networks 5 , 6 . Intermolecular interactions of biological molecules and inorganic nanoparticles show some commonalities 7 – 9 , but these structures differ in scale, in geometry and in the dynamics of chiral shapes, which can both impede and strengthen their mirror-asymmetric complexes. Here we show that achiral and left- and right-handed gold biomimetic nanoparticles show different in vitro and in vivo immune responses. We use irradiation with circularly polarized light (CPL) to synthesize nanoparticles with controllable nanometre-scale chirality and optical anisotropy factors ( g -factors) of up to 0.4. We find that binding of nanoparticles to two proteins from the family of adhesion G-protein-coupled receptors (AGPCRs)—namely cluster-of-differentiation 97 (CD97) and epidermal-growth-factor-like-module receptor 1 (EMR1)—results in the opening of mechanosensitive potassium-efflux channels, the production of immune signalling complexes known as inflammasomes, and the maturation of mouse bone-marrow-derived dendritic cells. Both in vivo and in vitro immune responses depend monotonically on the g -factors of the nanoparticles, indicating that nanoscale chirality can be used to regulate the maturation of immune cells. Finally, left-handed nanoparticles show substantially higher (1,258-fold) efficiency compared with their right-handed counterparts as adjuvants for vaccination against the H9N2 influenza virus, opening a path to the use of nanoscale chirality in immunology. Nanoparticles with different chiralities have different in vitro and in vivo effects on the immune system, suggesting new ways of creating vaccine adjuvants.

The prevalence and mortality rates of acute kidney injury (AKI) remain high, with ischemia-reperfusion (I/R) being a major cause in clinical settings. Dendritic cells (DCs) play a crucial role in inducing the infiltration of inflammatory cells into the kidneys during I/R, leading to persistent kidney damage. However, immature DCs (imDCs) maintain self-tolerance under homeostatic conditions. Therefore, targeting the immunomodulatory duality of DCs to prevent I/R-AKI is of significant importance. In this study, we found Pre-treatment of bone marrow-derived dendritic cells (BMDCs) with the EP4 receptor agonist L-902,688 induced the generation of EP4 high CCR7 high DC (LDC), However, there was a decrease in its maturation markers (CD80, CD86, and MHCII). Additionally, treatment with the EP4 receptor antagonist GW 627,368 resulted in reduced CCR7 expression on DCs without significantly affecting DC maturation. Furthermore, levels of pro-inflammatory cytokines decreased in the supernatant of LDCs while secretion of the anti-inflammatory cytokine IL-10 surged, indicating that LDCs possess stronger immune tolerance. Subsequent co-culturing mouse renal tubular epithelial cells TCMK-1 with LDCs did not impair TCMK-1 cells viability but rather enhanced cell migration rates. Following hypoxia-reoxygenation (H/R) treatment, TCMK-1 cells co-cultured with LDCs exhibited reduced intracellular ROS levels, improved oxidative stress response, reduced apoptosis, and preserved migratory capacity. In addition, our in vivo pharmacological intervention experiments manifested that the preemptive activation of the EP4 receptor conferred remarkable renal protection by inhibiting renal DC maturation. Collectively, our findings further investigate the involvement of PGE2-EP4 signaling in the regulation of DC immune function, emphasizing the potential benefits of targeting the PGE2-EP4-DC axis for preventing I/R-AKI.

Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. ClinicalTrials.gov NCT01573312.

Respiratory infection with highly pathogenic influenza A viruses is characterized by the exuberant production of cytokines and chemokines and the enhanced recruitment of innate inflammatory cells. Here, we show that challenging mice with virulent influenza A viruses, including currently circulating H5N1 strains, causes the increased selective accumulation of a particular dendritic cell subset, the tipDCs, in the pneumonic airways. These tipDCs are required for the further proliferation of influenza-specific CD8⁺ T cells in the infected lung, because blocking their recruitment in CCR2⁻/⁻ mice decreases the numbers of CD8⁺ effectors and ultimately compromises virus clearance. However, diminution rather than total elimination of tipDC trafficking by treatment with the peroxisome proliferator-activated receptor-γ agonist pioglitazone moderates the potentially lethal consequences of excessive tipDC recruitment without abrogating CD8⁺ T cell expansion or compromising virus control. Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic.

DC-SIGN, a C-type lectin mainly expressed in dendritic cells (DCs), has been reported to mediate several viral infections. We previously reported that DC-SIGN mediated H5N1 influenza A virus (AIVs) infection, however, the important DC-SIGN interaction with N-glycosylation sites remain unknown. This study aims to identify the optimal DC-SIGN interacting N-glycosylation sites in HA proteins of H5N1-AIVs. Results from NetNGlyc program analyzed the H5 hemagglutinin sequences of isolates during 2004–2020, revealing that seven and two conserved N-glycosylation sites were detected in HA1 and HA2 domain, respectively. A lentivirus pseudotyped A/Vietnam/1203/04 H5N1 envelope (H5N1-PVs) was generated which displayed an abundance of HA5 proteins on the virions via immuno-electron microscope observation. Further, H5N1-PVs or reverse-genetics (H5N1-RG) strains carrying a serial N-glycosylated mutation was generated by site-directed mutagenesis assay. Human recombinant DC-SIGN (rDC-SIGN) coated ELISA showed that H5N1-PVs bound to DC-SIGN, however, mutation on the N27Q, N39Q, and N181Q significantly reduced this binding (p < 0.05). Infectivity and capture assay demonstrated that N27Q and N39Q mutations significantly ameliorated DC-SIGN mediated H5N1 infection. Furthermore, combined mutations (N27Q&N39Q) significantly waned the interaction on either H5N1-PVs or -RG infection in cis and in trans (p < 0.01). This study concludes that N27 and N39 are two essential N-glycosylation contributing to DC-SIGN mediating H5N1 infection.

Prostaglandins play a key role in inflammation in a variety of settings. Now, Shuh Narumiya and colleagues show that prostaglandin E2 drives the production of inflammatory T helper cells, and that this can be blocked by inhibiting its EP4 receptor subtype. EP4 inhibitors were also effective at inhibiting disease pathogenesis in animal models of two inflammatory diseases. Two distinct helper T (T H ) subsets, T H 1 and T H 17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these T H subsets in human diseases, suggest the need for pharmacological measures to manipulate these T H subsets. Here we show that prostaglandin E 2 (PGE 2 ) acting on its receptor EP4 on T cells and dendritic cells not only facilitates T H 1 cell differentiation but also amplifies interleukin-23–mediated T H 17 cell expansion in vitro . Administration of an EP4-selective antagonist in vivo decreases accumulation of both T H 1 and T H 17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE 2 -EP4 signaling promotes immune inflammation through T H 1 differentiation and T H 17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.