Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.

• MeSH
• Spondylitis, Ankylosing * drug therapy   MeSH
• Epitopes MeSH
• HLA-B Antigens MeSH
• Immunotherapy MeSH
• Tumor Necrosis Factor Inhibitors therapeutic use   MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell genetics   therapeutic use   MeSH
• T-Lymphocytes MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Epitopes MeSH
• HLA-B Antigens MeSH
• Tumor Necrosis Factor Inhibitors MeSH
• Receptors, Antigen, T-Cell 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.

• Keywords
• T cell, T-cell receptor repertoires, aging, diversity, functional T-cell subsets,
• MeSH
• Immunity, Cellular physiology   MeSH
• Complementarity Determining Regions genetics   immunology   MeSH
• Mice MeSH
• T-Lymphocyte Subsets cytology   immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Complementarity Determining Regions MeSH

• MeSH
• Genetic Markers genetics   MeSH
• Gene Rearrangement * MeSH
• Genes, Immunoglobulin MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell genetics   MeSH
• Reproducibility of Results MeSH
• Neoplasm, Residual diagnosis   MeSH
• Models, Theoretical MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Genetic Markers MeSH
• Receptors, Antigen, T-Cell 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 .

• Keywords
• B-cell, Browser, High-throughput sequencing, Immunology, Repertoire sequencing, T-cell,
• MeSH
• B-Lymphocytes immunology   metabolism   MeSH
• Genomics methods   standards   MeSH
• Complementarity Determining Regions genetics   MeSH
• Web Browser MeSH
• Clonal Evolution genetics   MeSH
• Humans MeSH
• Cluster Analysis MeSH
• Software * MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• V(D)J Recombination * MeSH
• Computational Biology methods   standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Complementarity Determining Regions MeSH

Despite the growing number of immune repertoire sequencing studies, the field still lacks software for analysis and comprehension of this high-dimensional data. Here we report VDJtools, a complementary software suite that solves a wide range of T cell receptor (TCR) repertoires post-analysis tasks, provides a detailed tabular output and publication-ready graphics, and is built on top of a flexible API. Using TCR datasets for a large cohort of unrelated healthy donors, twins, and multiple sclerosis patients we demonstrate that VDJtools greatly facilitates the analysis and leads to sound biological conclusions. VDJtools software and documentation are available at https://github.com/mikessh/vdjtools.

• MeSH
• Child MeSH
• Adult MeSH
• Twins genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Receptors, Antigen, T-Cell chemistry   genetics   metabolism   MeSH
• Multiple Sclerosis genetics   MeSH
• Sequence Analysis, DNA methods   MeSH
• Cluster Analysis MeSH
• Software * MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Computational Biology methods   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Receptors, Antigen, T-Cell MeSH

BACKGROUND: The Immunoglobulins (IG) and the T cell receptors (TR) play the key role in antigen recognition during the adaptive immune response. Recent progress in next-generation sequencing technologies has provided an opportunity for the deep T cell receptor repertoire profiling. However, a specialised software is required for the rational analysis of massive data generated by next-generation sequencing. RESULTS: Here we introduce tcR, a new R package, representing a platform for the advanced analysis of T cell receptor repertoires, which includes diversity measures, shared T cell receptor sequences identification, gene usage statistics computation and other widely used methods. The tool has proven its utility in recent research studies. CONCLUSIONS: tcR is an R package for the advanced analysis of T cell receptor repertoires after primary TR sequences extraction from raw sequencing reads. The stable version can be directly installed from The Comprehensive R Archive Network ( http://cran.r-project.org/mirrors.html ). The source code and development version are available at tcR GitHub ( http://imminfo.github.io/tcr/ ) along with the full documentation and typical usage examples.

• MeSH
• Immunoglobulins genetics   MeSH
• Humans MeSH
• Programming Languages MeSH
• Receptors, Antigen, T-Cell genetics   immunology   MeSH
• Sequence Analysis, DNA methods   MeSH
• Software * MeSH
• High-Throughput Nucleotide Sequencing methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Immunoglobulins MeSH
• Receptors, Antigen, T-Cell MeSH

Deep profiling of antibody and T cell-receptor repertoires by means of high-throughput sequencing has become an attractive approach for adaptive immunity studies, but its power is substantially compromised by the accumulation of PCR and sequencing errors. Here we report MIGEC (molecular identifier groups-based error correction), a strategy for high-throughput sequencing data analysis. MIGEC allows for nearly absolute error correction while fully preserving the natural diversity of complex immune repertoires.

• MeSH
• DNA Fingerprinting methods   standards   MeSH
• Polymerase Chain Reaction standards   MeSH
• Receptors, Antigen, T-Cell genetics   MeSH
• High-Throughput Nucleotide Sequencing standards   MeSH
• Research Design * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Receptors, Antigen, T-Cell MeSH

• Keywords
• NGS data analysis, TCR beta, TCR repertoire, adaptive immunity, overlap,
• Publication type
• Journal Article MeSH