A balanced immune response is a cornerstone of healthy aging. Here, we uncover distinctive features of the long-lived blind mole-rat (Spalax spp.) adaptive immune system, relative to humans and mice. The T-cell repertoire remains diverse throughout the Spalax lifespan, suggesting a paucity of large long-lived clones of effector-memory T cells. Expression of master transcription factors of T-cell differentiation, as well as checkpoint and cytotoxicity genes, remains low as Spalax ages. The thymus shrinks as in mice and humans, while interleukin-7 and interleukin-7 receptor expression remains high, potentially reflecting the sustained homeostasis of naive T cells. With aging, immunoglobulin hypermutation level does not increase and the immunoglobulin-M repertoire remains diverse, suggesting shorter B-cell memory and sustained homeostasis of innate-like B cells. The Spalax adaptive immune system thus appears biased towards sustained functional and receptor diversity over specialized, long-lived effector-memory clones-a unique organizational strategy that potentially underlies this animal's extraordinary longevity and healthy aging.

• MeSH
• adaptivní imunita MeSH
• imunoglobuliny metabolismus   MeSH
• interleukin-7 metabolismus   MeSH
• lidé MeSH
• mikroftalmičtí podzemní hlodavci MeSH
• myši MeSH
• Spalax * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imunoglobuliny MeSH
• interleukin-7 MeSH

Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type one diabetes responsive TCR[Formula: see text] sequences .

• Klíčová slova
• computational biology, condition associated receptors, human, immunology, inflammation, repertoire sequencing, statistical analysis, systems biology,
• MeSH
• adaptivní imunita genetika   MeSH
• Cytomegalovirus imunologie   MeSH
• diabetes mellitus genetika   imunologie   MeSH
• genetická variace imunologie   MeSH
• hypervariabilní oblasti genetika   MeSH
• lidé MeSH
• receptory antigenů B-buněk genetika   MeSH
• receptory antigenů T-buněk genetika   imunologie   MeSH
• receptory antigenů genetika   imunologie   MeSH
• receptory imunologické genetika   imunologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hypervariabilní oblasti MeSH
• receptory antigenů B-buněk MeSH
• receptory antigenů T-buněk MeSH
• receptory antigenů MeSH
• receptory imunologické MeSH

For understanding the rules and laws of adaptive immunity, high-throughput profiling of T-cell receptor (TCR) repertoires becomes a powerful tool. The structure of TCR repertoires is instructive even before the antigen specificity of each particular receptor becomes available. It embodies information about the thymic and peripheral selection of T cells; the readiness of an adaptive immunity to withstand new challenges; the character, magnitude and memory of immune responses; and the aetiological and functional proximity of T-cell subsets. Here, we describe our current analytical approaches for the comparative analysis of murine TCR repertoires, and show several examples of how these approaches can be applied for particular experimental settings. We analyse the efficiency of different metrics used for estimation of repertoire diversity, repertoire overlap, V-gene and J-gene segments usage similarity, and amino acid composition of CDR3. We discuss basic differences of these metrics and their advantages and limitations in different experimental models, and we provide guidelines for choosing an efficient way to lead a comparative analysis of TCR repertoires. Applied to the various known and newly developed mouse models, such analysis should allow us to disentangle multiple sophisticated puzzles in adaptive immunity.

• Klíčová slova
• T cell, T-cell receptor repertoires, aging, diversity, functional T-cell subsets,
• MeSH
• buněčná imunita fyziologie   MeSH
• hypervariabilní oblasti genetika   imunologie   MeSH
• myši MeSH
• T-lymfocyty - podskupiny cytologie   imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• hypervariabilní oblasti MeSH

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

• MeSH
• antigeny nádorové MeSH
• buněčné mikroprostředí MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• chronická lymfatická leukemie imunologie   MeSH
• genová přestavba T-lymfocytů MeSH
• geny pro imunoglobuliny MeSH
• lidé MeSH
• senioři MeSH
• T-lymfocyty imunologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH

The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a "public" repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pre-natal life, and survive over long periods, providing the basis of the public repertoire.

• MeSH
• antigenní specifita receptorů T-buněk genetika   MeSH
• dvojčata monozygotní genetika   MeSH
• genetická variace genetika   MeSH
• genová přestavba T-lymfocytů genetika   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• receptory antigenů T-buněk fyziologie   MeSH
• rekombinace genetická MeSH
• sekvence nukleotidů MeSH
• stárnutí genetika   imunologie   MeSH
• vývojová regulace genové exprese genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptory antigenů T-buněk MeSH

BACKGROUND: The repertoire of T- and B-cell receptor sequences encodes the antigen specificity of adaptive immunity system, determines its present state and guides its ability to mount effective response against encountered antigens in future. High throughput sequencing of immune repertoires (Rep-Seq) is a promising technique that allows to profile millions of antigen receptors of an individual in a single experiment. While a substantial number of tools for mapping and assembling Rep-Seq data were published recently, the field still lacks an intuitive and flexible tool that can be used by researchers with little or no computational background for in-depth analysis of immune repertoire profiles. RESULTS: Here we report VDJviz, a web tool that can be used to browse, analyze and perform quality control of Rep-Seq results generated by various pre-processing software. On a set of real data examples we show that VDJviz can be used to explore key repertoire characteristics such as spectratype, repertoire clonality, V-(D)-J recombination patterns and to identify shared clonotypes. We also demonstrate the utility of VDJviz in detection of critical Rep-Seq biases such as artificial repertoire diversity and cross-sample contamination. CONCLUSIONS: VDJviz is a versatile and lightweight tool that can be easily employed by biologists, immunologists and immunogeneticists for routine analysis and quality control of Rep-Seq data. The software is freely available for non-commercial purposes, and can be downloaded from: https://github.com/antigenomics/vdjviz .

• Klíčová slova
• B-cell, Browser, High-throughput sequencing, Immunology, Repertoire sequencing, T-cell,
• MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• genomika metody   normy   MeSH
• hypervariabilní oblasti genetika   MeSH
• internetový prohlížeč MeSH
• klonální evoluce genetika   MeSH
• lidé MeSH
• shluková analýza MeSH
• software * MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• V(D)J rekombinace * MeSH
• výpočetní biologie metody   normy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hypervariabilní oblasti MeSH

• Klíčová slova
• NGS data analysis, TCR beta, TCR repertoire, adaptive immunity, overlap,
• Publikační typ
• časopisecké články MeSH