Sulfonium-Stapled Peptides-Based Neoantigen Delivery System for Personalized Tumor Immunotherapy and Prevention.

Neoantigen peptides hold great potential as vaccine candidates for tumor immunotherapy. However, due to the limitation of antigen cellular uptake and cross-presentation, the progress with neoantigen peptide-based vaccines has obviously lagged in clinical trials. Here, a stapling peptide-based nano-vaccine is developed, comprising a self-assembly nanoparticle driven by the nucleic acid adjuvant-antigen conjugate.

SIGANEO: Similarity network with GAN enhancement for immunogenic neoepitope prediction.

Target selection of the personalized cancer neoantigen vaccine, which is highly dependent on computational prediction algorithms, is crucial for its clinical efficacy. Due to the limited number of experimentally validated immunogenic neoepitopes as well as the complexity of neoantigens in eliciting T cell response, the accuracy of neoepitope immunogenicity prediction methods requires persistent efforts for improvement. We present a deep learning framework for neoepitope immunogenicity prediction - SIGANEO by integrating GAN-like network with similarity network to address issues of missing values and limited data concerning neoantigen prediction.

Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.

Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage.

Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches.

Tissue-resident memory T (T ) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive T differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 T across both skin and small-intestine intraepithelial lymphocytes (siIEL).

Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2.

Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling.

Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.

Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity. Pore formation is triggered by gasdermin cleavage. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown.

The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by .

Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor-β-activated kinase 1 (TAK1) by pathogenic in macrophages triggers receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen to uncover mediators of caspase-8-dependent pyroptosis identified an unexpected role of the lysosomal FLCN-FNIP2-Rag-Ragulator supercomplex, which regulates metabolic signalling and the mechanistic target of rapamycin complex 1 (mTORC1).

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis.

Background: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD).

Objective: We aimed to investigate the role of NKT cells in AD development, especially in skin.

MATHLA: a robust framework for HLA-peptide binding prediction integrating bidirectional LSTM and multiple head attention mechanism.

Background: Accurate prediction of binding between class I human leukocyte antigen (HLA) and neoepitope is critical for target identification within personalized T-cell based immunotherapy. Many recent prediction tools developed upon the deep learning algorithms and mass spectrometry data have indeed showed improvement on the average predicting power for class I HLA-peptide interaction. However, their prediction performances show great variability over individual HLA alleles and peptides with different lengths, which is particularly the case for HLA-C alleles due to the limited amount of experimental data.

Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge.

Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.

FABP5 as a possible biomarker in atopic march: FABP5-induced Th17 polarization, both in mouse model and human samples.

Background: While the incidence of patients with atopic dermatitis (AD) with atopic march (AM) showing respiratory allergy is steadily rising, the pathomechanism is still unknown. There are currently no biomarkers to predict progression of AM.

Methods: To explore the mechanism of AM, patients with AD and AM and healthy controls were recruited and RNA microarray, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were performed.

A mutation that blocks integrin αβ activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Background: β integrins are responsible for the efficient recruitment of lymphocytes from the blood and their retention in gut-associated lymphoid tissues. Integrin αβ binds MAdCAM-1, mediating rolling adhesion of lymphocytes on blood vessel walls when inactive and firm adhesion when activated, thereby controlling two critical steps of lymphocyte homing to the gut. By contrast, integrin αβ mediates the adhesion of lymphocytes to gut epithelial cells by interacting with E-cadherin.

IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors.

We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β, IL1α, and IL1R1 mice. Tumors grew progressively in IL1R and IL1α mice but were often absent in IL1β mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages.

Publisher Correction: Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling.

In this Letter, Supplementary Fig. 1 was missing. This error has been corrected online.

Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling.

Cytosolic DNA triggers innate immune responses through the activation of cyclic GMP-AMP synthase (cGAS) and production of the cyclic dinucleotide second messenger 2',3'-cyclic GMP-AMP (cGAMP). 2',3'-cGAMP is a potent inducer of immune signalling; however, no intracellular nucleases are known to cleave 2',3'-cGAMP and prevent the activation of the receptor stimulator of interferon genes (STING). Here we develop a biochemical screen to analyse 24 mammalian viruses, and identify poxvirus immune nucleases (poxins) as a family of 2',3'-cGAMP-degrading enzymes.

A Comprehensive Survey of Immune Cytolytic Activity-Associated Gene Co-Expression Networks across 17 Tumor and Normal Tissue Types.

Cytolytic immune activity in solid tissue can be quantified by transcript levels of two genes, and , which is named the CYT score. A previous study has investigated the molecular and genetic properties of tumors associated CYT, but a systematic exploration of how co-expression networks across different tumors are shaped by anti-tumor immunity is lacking. Here, we examined the connectivity and biological themes of CYT-associated modules in gene co-expression networks of 14 tumor and 3 matched normal tissues constructed from the RNA-Seq data of the "The Cancer Genome Atlas" project.

Metabolic Reprogramming and Longevity of Tissue-Resident Memory T Cells.

Tissue-resident memory T cells (T) persist in peripheral tissues for long periods of time in the absence of antigenic stimulation. Upon re-encounter with cognate antigen, T trigger an immediate immune response at the local tissue microenvironment and provide the first line of host defense. T have been reported to play significant roles in host antimicrobial infection, cancer immunotherapy, and pathogenesis of a number of human autoimmune diseases, such as psoriasis, vitiligo, and atopic dermatitis.

PNPT1 Release from Mitochondria during Apoptosis Triggers Decay of Poly(A) RNAs.

Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3' end, triggered by the mitochondrial intermembrane space 3'-to-5' exoribonuclease PNPT1, released during MOMP.

Staged development of long-lived T-cell receptor αβ T17 resident memory T-cell population to Candida albicans after skin infection.

Background: Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (T) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects.

Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.

Tissue-resident memory T (T) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of T cells are obscure. Here we show that mouse CD8 T cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5).

Static Compression Induces ECM Remodeling and Integrin α2β1 Expression and Signaling in a Rat Tail Caudal Intervertebral Disc Degeneration Model.

Study Design: A three-level rat tail caudal intervertebral disc (IVD) degeneration (IVDD) model was established to study effects of static compression on extracellular matrix (ECM) remodeling and integrin signaling in IVDs during IVDD.

Objective: The aim of this study was to investigate the effect of compression force on ECM remodeling and integrin signaling in IVDs during IVDD.

Summary Of Background Data: Integrins sense mechanical environment alteration via binding to ECM ligands and trigger intracellular signaling for pathological ECM remodeling during IVDD.

Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta.

Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores.

Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation.

Sensing and responding to cytosolic viruses invasions: An orchestra of kaleidoscopic ubiquitinations.

Ubiquitin is a versatile molecular signature that modulates diverse cellular processes via proteasome-dependent and proteasome-independent mechanisms. The covalent and/or non-covalent binding of mono-ubiquitin and/or poly-ubiquitin chains to a target protein broadens the dynamic and functional spectra for signal integration. Different linkages of poly-ubiquitin chains determine specific physiological or pathological functions of target proteins.