International Immunology

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Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD), and found 31 missense disease-associated SNPs by whole-exome sequencing...

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two SNPs associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors, and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement...

Intestinal macrophages with functional plasticity play essential roles in gut immune responses by increasing chemokines and cytokines, thereby contributing to the pathogenesis of inflammatory bowel disease (IBD). Poly(rC)-binding protein 1 (PCBP1), which is widely expressed in immune cells, binds to nucleic acids in mRNA processing, stabilization, translation, and transcription. However, little is known about the influence of PCBP1 on macrophages and its specific mechanism in inflamed intestines. In this study, conditional depletion of Pcbp1 in macrophages protected mice from progression of dextran sulfate sodium(DSS) -induced colitis and resulted in significant alleviation of colitis...

The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation...

T-cell independent type II (TI-II) antigens, such as capsular polysaccharides, have multivalent epitope, which induce B cell activation, plasma cell differentiation and antibody production by strongly cross-linking B-cell receptors. However, the mechanism of B cell activation by TI-II antigens remains unclear. In this study, we demonstrate that DNA endonuclease DNase1L3 (also termed DNase γ) is required for the TI-II response. The production of antigen-specific antibodies was severely diminished in DNase1L3-deficient mice upon immunization with TI-II antigens, but not with TD antigens...

Immunogenicity can be evaluated by detecting antibodies induced by an antigen. Presently deployed assays, however, do not consider the negative impacts of antibody poly-specificity, which is well-established at the monoclonal antibody level. Here, we studied antibody poly-specificity at the serum level (i.e., non-specific Antibody (Ab)-probe interactions, NSIs), and ended up with establishing a new platform for viral peptide immunogenicity evaluation. We first selected three peptides of high, medium, and low immunogenicity, using "vaccine serum response rate"-based approach (i...

BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class-switch and affinity-maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively...

Vaccination for the prevention of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is considered the most promising approach to control the pandemic of coronavirus disease 2019 (COVID-19). Although various COVID-19 vaccines have been developed worldwide using several modalities, the vaccines that have shown the highest efficacy to date are mRNA vaccines. Despite their extensive usage, the mechanisms that stimulate the immune responses associated with their immunogenicity and reactogenicity remain largely unknown...

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of FDA-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death...

Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions caused by infections, allergic responses, autoimmunity, and tissue damage. Many cell types in the peripheral immune system express OPN with various functions, which could be beneficial or detrimental. Also, more recent studies demonstrated that OPN is highly expressed in the central nervous system (CNS), particularly in microglia during CNS diseases and development...

The RNA-binding proteins Roquin-1/2 and Regnase-1 exert essential regulation by controlling proinflammatory mRNA expression to prevent autoimmune disease. More recently, inhibition of this post-transcriptional gene regulatory program has been demonstrated to enable enhanced anti-tumor responses by tumor antigen-specific CD8 + T cells. In this review we describe the functions of these RNA-binding proteins and the phenotypes that arise in association with genetic inhibition or inactivation. We discuss how inducible inactivation of the system reprograms CD4 + and CD8 + T cell fates by changing cell metabolism, activation, differentiation or effector/memory decisions...

CD8αα + intestinal intraepithelial lymphocytes (iIELs) are known for their unique role in keeping the integrity of the intestinal epithelial barrier, but factors affecting the development of these cells have not been thoroughly understood. Here we found that the transcriptional regulator interferon regulatory factor-2 (IRF-2) plays a cell-intrinsic, indispensable role in establishing iIEL populations. CD8αα +, but not CD8αβ +, iIELs bearing TCRαβ or TCRγδ were severely reduced in numbers in mice lacking this factor (Irf2-/- mice)...

Group 1 innate lymphoid cells (G1-ILCs) are innate immune effectors critical for the response to intracellular pathogens and tumors. G1-ILCs comprise circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s). ILC1s mainly reside in barrier tissues and provide the initial sources of interferon-γ (IFN-γ) to prime the protecting responses against infections, that are followed by the response of recruited NK cells. Despite such distribution differences, whether local environmental factors influence the behavior of NK cells and ILC1s is unclear...

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that catalyzes adenosine-to-inosine conversions in double-stranded RNAs (dsRNAs). In mammals, ADAR1 is composed of two isoforms: a nuclear short p110 isoform and a cytoplasmic long p150 isoform. Whereas both isoforms contain right-handed dsRNA-binding and deaminase domains, ADAR1 p150 harbors a Zα domain that binds to left-handed dsRNAs, termed Z-RNAs. MDA5 sensing of endogenous dsRNAs as non-self leads to the induction of type I interferon (IFN)-stimulated genes, but recent studies revealed that ADAR1 p150-mediated RNA editing, but not ADAR1 p110, prevents this MDA5-mediated sensing...

The immune evasion of SARS-CoV-2 Omicron variants caused by multiple amino acid replacements in the receptor-binding domain (RBD) of spike protein wanes the effectiveness of antibodies elicited by current SARS-CoV-2 booster vaccination. The vaccines that target Omicron strains have been recently developed, however, there has been a concern yet to be addressed regarding the negative aspect of the immune response known as original antigenic sin. Here we demonstrate that the breadth of neutralizing antibodies against SARS-CoV-2 variants is barely elicited by immunizing monovalent viral antigens via vaccination or natural infection in mice and human subjects...

Dendritic cells (DCs) express major histocompatibility complex class II (MHC-II) and are best known for proficiently presenting antigens to T cells, thereby eliciting specific adaptive T cell responses. Moreover, conventional DCs are specifically adept at handling intestinal antigens. Relatively recent discoveries and investigations have proven the existence of a new group of innate lymphocytes that reside in tissues like the intestine. They lack specific antigen-receptors and can express MHC-II. These group 3 innate lymphoid cells (ILC3s) comprise a subset of heterogeneous innate lymphocytes that mirror the phenotype and functions of T-helper cells and act in the first line of defense...

Innate immunity is the first line of host defense against pathogenic invasion in metazoans. The transcription factor BATF3 plays a crucial role in the development of conventional dendritic cells and the program of CD8 + T cell survival and memory, but the role of BATF3 in innate immunity response remains unclear. Here, we show an evolutionarily conserved basic-region leucine zipper (bZIP) transcription factor BATF3/ZIP-10 suppresses innate immune response through repressing p38/PMK-1 MAPK pathway in vitro and in vivo...

T cells are activated by antigen and costimulatory receptor signaling and undergo robust proliferation and differentiation into effector cells with protective function. Such quantitatively and qualitatively amplified T cell responses are effective in controlling acute infection and are followed by contraction of the effector population and the formation of resting memory T cells for enhanced protection against previously experienced antigen. However, in the face of persistent antigen during chronic viral infection, in autoimmunity, or in the tumor microenvironment, T cells exhibit distinct responses relative to those in acute insult in several aspects, including reduced clonal expansion and impaired effector function associated with inhibitory receptor expression, a state known as exhaustion...

Dysregulation of osteoclasts, the multinucleated cells responsible for bone resorption, contributes to several degenerative bone disorders. Previously, we showed that blocking the leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4), a kind of inhibitory receptor that plays an important role in immune regulation, promotes osteoclast differentiation in vitro. Here, we explored whether gp49B, the murine ortholog of LILRB4, regulates osteoclastogenesis in vivo, and whether fibronectin (FN), a ligand of LILRB4/gp49B, certainly contributes to LILRB4/gp49B-mediated osteoclastogenesis...