IMGT^®, the international ImMunoGeneTics information system^®, http://www.imgt.org/, is at the forefront of the immunogenetics and immunoinformatics fields with more than 30 years of experience. IMGT^® makes available databases and tools to the scientific community pertaining to the adaptive immune response, based on the IMGT-ONTOLOGY. We focus on the recent features of the IMGT^® databases, tools, reference directories and web resources, within the three main axes of IMGT^® research and development. Axis I consists in understanding the adaptive immune response, by deciphering the identification and characterization of the immunoglobulin (IG) and T cell receptor (TR) genes in jawed vertebrates. It is the starting point of the two other axes, namely the analysis and exploration of the expressed IG and TR repertoires based on comparison with IMGT reference directories in normal and pathological situations (Axis II) and the analysis of amino acid changes and functions of 2D and 3D structures of antibody and TR engineering (Axis III).

Notch family proteins play a key role in a variety of developmental processes by controlling cell fate decisions and operating in a great number of biological processes in several organ systems, such as hematopoiesis, somatogenesis, vasculogenesis, neurogenesis and homeostasis. The Notch signaling pathway is crucial for the majority of developmental programs and regulates multiple pathogenic processes. Notch family receptors’ activation has been largely related to its multiple effects in sustaining oncogenesis. The Notch signaling pathway constitutes an ancient and conserved mechanism for cell to cell communication. Much of what is known about Notch family proteins function comes from studies done inCaenorhabditis ElegansandDrosophila Melanogaster. Although,humanNotch homologs had also been identified, the molecular mechanisms which modulate the Notch signaling pathway remained substantially unknown. In this study, an updated evolutionary analysis of the Notch family members among 603 different organisms of all kingdoms, frombacteriatohumans, was performed in order to discover key regions that have been conserved throughout evolution and play a major role in the Notch signaling pathway. The major goal of this study is the presentation of a novel updated phylogenetic tree for the Notch family as a reliable phylogeny “map”, in order to correlate information of the closely related members and identify new possible pharmacological targets that can be used in pathogenic cases, including cancer.

The adaptive immune system, along with the innate immune system, are the two main biological processes that protect an organism from pathogens. The adaptive immune system is characterized by the specificity and extreme diversity of its antigen receptors. These antigen receptors are the immunoglobulins (IG) or antibodies of the B cells and the T cell receptors (TR) of the T cells. The IG are proteins that have a dual role in immunity: they recognize antigens and trigger elimination mechanisms, to rid the body of foreign cells. The synthesis of the immunoglobulin heavy and light chains requires gene rearrangements at the DNA level in the IGH, IGK, and IGL loci. The rhesus monkey (Macaca mulatta) is one of the most widely used nonhuman primate species in biomedical research. In this manuscript, we provide a thorough analysis of the three IG loci of the Mmul_10 assembly of rhesus monkey, integrating IMGT previously existing data. Detailed characterization of IG genes includes their localization and position in the loci, the determination of the allele functionality, and the description of the regulatory elements of their promoters as well as the sequences of the conventional recombination signals (RS). This complete annotation of the genomic IG loci of Mmul_10 assembly and the highly detailed IG gene characterization could be used as a model, in additional rhesus monkey assemblies, for the analysis of the IG allelic polymorphism and structural variation, which have been described in rhesus monkeys.

The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to lack natural killer (NK) cells, γδ T cell-based immunity has been suggested in this species, which could represent an important arm of the immune system for antitumor responses. Here, we investigate the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell gene expression analysis. Using our own TCR annotation in the naked mole-rat genome, we report that the γδ TCR repertoire is dominated by a public invariant Vγ4-2/Vδ1-4 TCR, containing the complementary-determining-region-3 (CDR3)γ CTYWDSNYAKKLF / CDR3δ CALWELRTGGITAQLVF that are likely generated by short-homology-repeat-driven DNA rearrangements. This invariant TCR is specifically found in γδ T cells expressing genes associated with NK cytotoxicity and is generated in both the thoracic and cervical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vγ4-2/Vδ1-4 NK-like effector T cells in the naked mole-rat can contribute to tumor immunosurveillance by γδ TCR-mediated recognition of a common molecular signal.

IMGT®, the international ImMunoGeneTics information system®, has advanced its comprehensive platform for the analysis of immunoglobulin (IG) and T-cell receptor (TR) genes through the development of new automated and scalable tools. This article presents major updates aligned with IMGT’s three axes of research. Axis I introduces dynamic resources such as IMGT/GeneTables, IMGT/AssemblyComparison, IMGT/CDRLengths, IMGT/MultiGenomeViewer, enabling real-time access to annotated genomic data, and IMGT/StatAssembly to assess quality of IG/TR loci in assemblies. Axis II enhances repertoire analysis with a redesigned IMGT/GeneFrequency tool and new customization features in IMGT/V-QUEST, supporting flexible exploration of IG and TR gene expression. Axis III improves the accurate prediction of peptide–MHC thanks to IMGT/RobustpMHC. Additionally, the IMGT knowledge graph and its therapeutic extension, IMGT/mAb-KG, provide semantically structured access to >100 million immunogenetic triplets, integrating IMGT databases and linking IMGT content to external biomedical resources. These developments promote standardization, interoperability, and integrative analysis across immunogenetics and clinical applications, reinforcing IMGT’s (accessible at https://www.imgt.org) role as a core reference in the era of FAIR data and personalized medicine.

Unraveling the genetic complexity of the human immunoglobulin heavy (IGH) chain locus provides valuable insights into the mechanisms underlying the efficacy and specificity of the adaptive immune response. Despite its crucial role, the IGH locus remains insufficiently characterized, with its allelic diversity and polymorphisms inadequately investigated. In this study, we present an analysis of the human IGH locus, incorporating 15 human genome assemblies from diverse ancestries, including African, European, Asian, Saudi, and mixed backgrounds. Through our examination of both maternal and paternal assemblies, we uncover novel IGH alleles, copy number variations (CNV), and polymorphisms, particularly within the variable (IGHV) region. Our findings reveal extensive and previously uncharacterized genetic variability in the constant (IGHC) region and distinct IMGT CNV forms across individuals. This research contributes to a significant enrichment of the IMGT® IGH reference directory, databases, tools and web resources, and lays the groundwork for an IMGT® haplotype database which can be progressively enriched as additional datasets become available. Such a resource promises to propel personalized immunogenomics forward, with exciting applications in cancer immunotherapy, COVID-19, and other immune-related diseases.