Yuri B Lebedev

Russian Academy of Sciences | RAS · M.M. Shemyakin–Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Spondyloarthritis (SpA) comprises a number of inflammatory rheumatic diseases with overlapping clinical manifestations. Strong association with several HLA-I alleles and T cell infiltration into an inflamed joint suggest involvement of T cells in SpA pathogenesis. In this study, we performed high-throughput T cell repertoire profiling of synovial f...

Retroelements (RE) have been proposed as important players in cancerogenesis. Different cancer types are characterized by a different level of tumor-specific RE insertions. In previous studies, small cohorts of hematological malignancies, such as acute myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia have been characterized by a...

Background Different studies show involvement of T-cells in pathogenesis of spondyloarthropathies (SpAs) - a group of rheumatic diseases strongly associated with presence of several MHC-I alleles (HLA-B*27, -B*38, -B*39, etc). Recently we and others identified a specific T-cell receptor motif in blood and synovial fluid of HLA-B*27+ AS patients tha...

High-throughput sequencing of immune receptor repertoires is a valuable tool for receiving insights in adaptive immunity studies. Several powerful methods for TCR/BCR repertoire reconstruction and analysis have been developed in the past decade. However, detection and correction of the discrepancy between real and experimentally observed lymphocyte...

T cells that express CD56 in peripheral blood of healthy humans represent a heterogeneous and poorly studied subset. In this work, we analyzed this subset for NKG2C expression. In both CD56 ⁺ and CD56 ⁻ subsets most of the NKG2C ⁺ T cells had a phenotype of highly differentiated CD8 ⁺ TEMRA cells. The CD56 ⁺ NKG2C ⁺ T cells also expressed a number...

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T cell response nor the diversity of resulting immun...

Background Retroelements (REs) occupy a significant part of all eukaryotic genomes including humans. The majority of retroelements in the human genome are inactive and unable to retrotranspose. Dozens of active copies are repressed in most normal tissues by various cellular mechanisms. These copies can become active in normal germline and brain tis...

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. The T cell response is a critical part of both individual and herd immunity to SARS-CoV-2 and the efficacy of developed vaccines. However neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T cell response nor the diversity of resulting immune memory are well under...

Introduction Clonality assessment using IG/TCR rearrangements is an essential tool for clonal evolution analysis and minimal residual disease monitoring in acute lymphoblastic leukemia (ALL). Here we present a new multiplex method for ALL clonal structures analysis at the single-cell level. Material and Methods: DNA from bone marrow (BM) samples of...

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. Using TCR alpha and beta repertoire sequencing for T-cell subsets, as well as single-cell RNAseq and TCRseq, we track the concentrations and phenotypes of individual T-cell clones in response to primary and secondary yellow fever immuniz...

Background and aims: Inflammatory bowel diseases (IBD) are chronic-remittent inflammatory diseases of the gastrointestinal tract. Disease development in IBD is still poorly understood and the search for the causative agents is ongoing. The intestinal inflammation in inflammatory bowel diseases (IBD) is thought to be T cell mediated and therefore de...

Background and aims: Intestinal inflammation in inflammatory bowel diseases (IBD) is thought to be T cell mediated and therefore dependent on the interaction between the T-cell receptor (TCR) and human leukocyte antigen (HLA) proteins expressed on antigen presenting cells.The collection of all TCRs in one individual, known as the TCR repertoire, i...

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. Previous studies show that secondary responses to the yellow fever vaccine - the model for acute infection in humans - are weaker than primary ones, but only quantitative measurements can describe the concentration changes and lineage fa...

Rearrangements of T‐ and B‐cell receptor (TCR and BCR) genes are useful markers for clonality assessment as well as for minimal residual disease (MRD) monitoring during the treatment of haematological malignancies. Currently, rearrangements of three out of four TCR and all BCR loci are used for this purpose. The fourth TCR gene, TRA, has not been u...

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR-disease associations. We present Antigen-sp...

Retroelements are considered as one of the important sources of genomic variability in modern humans. It is known that transposition activity of retroelements in germline cells generates new insertions in various genomic loci and sometimes results in genetic diseases. Retroelements activity in somatic cells is restricted by different cellular mecha...

Background There is increasing evidence that the transpositional activity of retroelements (REs) is not limited to germ line cells, but often occurs in tumor and normal somatic cells. Somatic transpositions were found in several human tissues and are especially typical for the brain. Several computational and experimental approaches for detection o...

Hypervariable T-cell receptors (TCR) play a key role in adaptive immunity, recognising a vast diversity of pathogen-derived antigens. High throughput sequencing of TCR repertoires (RepSeq) produces huge datasets of T-cell receptor sequences from blood and tissue samples. However, our ability to extract clinically relevant information from RepSeq da...

Hypervariable T-cell receptors (TCR) play a key role in adaptive immunity, recognising a vast diversity of pathogen-derived antigens. High throughput sequencing of TCR repertoires (RepSeq) produces huge datasets of T-cell receptor sequences from blood and tissue samples. However, our ability to extract clinically relevant information from RepSeq da...

Spondyloarthropathies (SpA) are a group of autoimmune diseases with similar clinical and genetic features, which includes ankylos- ing spondylitis (AS), psoriatic arthritis (PsA), enteropathic arthri- tis, undifferentiated SpA and reactive arthritis (ReA). Recently a characteristic TCRbeta motif represented by highly homologous CD8+ TRBV9+ clonotyp...

T-cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framew...

T-cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framew...

Recent studies of T-cell clonal repertoires of patients with ankylosing spondylitis (AS) have led to the discovery of AS-associated T-cell clones with a highly homologous T-cell receptor structure. The role of T-lymphocytes in the disease progression cannot be elucidated without analyzing the diversity and abundance of functionally different T-cell...

Autologous hematopoietic stem cell transplantation (HSCT), a safer type of HSCT than allogeneic HSCT, is a promising therapy for patients with severe autoimmune diseases (ADs). Despite the long history of medical practice, structural changes in the adaptive immune system as a result of autologous HSCT in patients with various types of ADs remain po...

Background There is increasing evidence that the transpositional activity of retroelements (REs) is not limited to germ line cells, but often occurs in tumor and normal somatic cells. Somatic transpositions were found in several human tissues and are especially typical for the brain. Several computational and experimental approaches for detection o...

Objective: The risk of AS is associated with genomic variants related to antigen presentation and specific cytokine signalling pathways, suggesting the involvement of cellular immunity in disease initiation/progression. The aim of the present study was to explore the repertoire of TCR sequences in healthy donors and AS patients to uncover AS-linke...

Vaccination against influenza is widely used to protect against seasonal flu epidemic although its effectiveness is debated. Here we performed deep quantitative T cell receptor repertoire profiling in peripheral blood of a healthy volunteer in response to trivalent subunit influenza vaccine. We did not observe significant rebuilding of peripheral b...

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 associ...

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 associ...

Number of shared out-of-frame alpha TCR CDR3 clonotypes reported between all 15 pairs of 6 donors consisting of 3 twin pairs (ordinate) compared to the model prediction (abscissa). To be able to compare datasets of different sizes, the sharing number was normalized by the product of the two cloneset sizes. The outlying three red circles represent t...

Number of shared out-frame beta TCR CDR3 clonotypes reported between all 15 pairs of 6 donors consisting of 3 twin pairs (ordinate) compared to the model prediction (abscissa). The three outlying red circles represent the twin pairs, while the black circles refer to pairs of unrelated individuals. Error bars show one standard deviation. (PDF)

Detailed description of experimental and data analysis procedures and supplementary results. (PDF)

Library preparation protocol. A) cDNA first strand synthesis for alpha and beta chains starts from specific primers in the C-segment conserved region. B) The template switching effect was used to introduce a universal primer binding site to the 3’cDNA end. The SMART-Mk sequence contains a sample barcode (black ellipse) for contamination control. C)...

Number of shared in-frame alpha TCR CDR3 clonotypes reported between all 15 pairs of 6 donors consisting of 3 twin pairs (ordinate) compared to the model prediction (abscissa). To be able to compare datasets of different sizes, the sharing number was normalized by the product of the two cloneset sizes. The three red circles represent the twin pairs...

Number of shared in-frame beta TCR CDR3 clonotypes reported between all 15 pairs of 6 donors consisting of 3 twin pairs (ordinate) compared to the model prediction (abscissa). To be able to compare datasets of different sizes, the sharing number was normalized by the product of the two cloneset sizes. The three outlying red circles represent the tw...

Reproducibility of our results using previously published data. Distribution of Pgen—the probability that a sequence is generated by the VJ recombination process—for shared out-of-frame TCR alpha clonotypes between individual A1 from [8] and the other five individuals. While the distribution of shared sequences between unrelated individuals (red cu...

Normalized sharing of out-of-frame zero insertion clonotypes. Number of shared out-frame alpha zero insertion TCR CDR3 clonotypes reported between all 15 pairs of 6 donors consisting of 3 twin pairs (ordinate) compared to the model prediction (abscissa). The three red circles represent the twin pairs, while the black circles refer to pairs of unrel...

Mean number of insertions in shared sequences in alpha out-of-frame repertoires of CD45RO+ (memory) cells. (PDF)

Dependence of mean insertion number on rank holds for different bin sizes. Mean numbers of insertions were obtained by analysing subsequent groups of 1000 (A) and 4000 (B) sequences of decreasing abundances, as in Fig 3A from the main text. (C,D,E) are results for ageing datasets reproduced for the top 1000, 2000 and 4000 clonotypes. Solid lines ar...

Mean number of insertions in shared sequences in alpha out-of-frame repertoires. (PDF)

The dependence between clone abundance and mean insertion number is robust across cord blood donors. Mean numbers of insertions were obtained by analysing groups of 3000 sequences of decreasing abundances as in Fig 3A, for 7 independent published cord blood samples from [24]. A similar decreasing trend is observed for all samples. (PDF)

List of primers used. (XLSX)

Rank-abundance dependencies. Here we show the dependence of the clone abundance on its abundance rank in samples from Fig 3A. Memory clones are typically larger than the naive and cord blood clones of same rank, possibly due to the history of clonal expansions. (PDF)

Number of reads, UMI and unique CDR3 nucleotide sequences in each sample. (XLSX)

Ageing data used for Fig 4 and exponential decay fits. Percentage of the naive T-cells defined using flow cytometry, see [23] for details. (XLSX)

Allogeneic transplantation of hematopoietic cells (HSCT) is an established method to treat different hematologic malignancies and disorders of hematopoietic and lymphoid system. Graft-versus-host-disease is one of the main risk factor for success of the procedure. Simultaneous depletion of alpha-beta T-cells and CD19+ cells in graft is the promisin...

αβT-cell depleted allogeneic hematopoietic cells transplantation holds promise for the safe and accessible therapy of both malignant and non-malignant blood disorders. Here we employed molecular barcoding-normalized T-cell receptor (TCR) profiling to quantitatively track T-cell immune reconstitution after TCRαβ/CD19-depleted transplantation in chil...

Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant neoplasm of the lymphocyte precursors that suffered malignant transformation arresting the lymphoid cell differentiation. Clinical studies revealed monoor, more rarely, oligoclonal nature of the disease. A precise identification of malignant clone markers is both the crucial sta...

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 pren...

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 pren...

Monitoring of minimal residual disease (MRD) proved to be a valuable tool for predicting relapse in patients with acute lymphoblastic leukemia (ALL). However, the universal use of MRD monitoring in routine clinical practice is limited because current MRD assays have some methodological difficulties, high price and ambiguity of assay results interpr...

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 analysi...

Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic ac...

Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individu...

The decrease of TCR diversity with aging has never been studied by direct methods. In this study, we combined high-throughput Illumina sequencing with unique cDNA molecular identifier technology to achieve deep and precisely normalized profiling of TCR β repertoires in 39 healthy donors aged 6-90 y. We demonstrate that TCR β diversity per 10(6) T c...

The relationship between maternal and child immunity has been actively studied in the context of complications during pregnancy, autoimmune diseases, and haploidentical transplantation of hematopoietic stem cells and solid organs. Here, we have for the first time used high-throughput Illumina HiSeq sequencing to perform deep quantitative profiling...

High-throughput sequencing has the power to reveal the nature of adaptive immunity as represented by the full complexity of T-cell receptor (TCR) and antibody (IG) repertoires, but is at present severely compromised by the quantitative bias, bottlenecks, and accumulated errors that inevitably occur in the course of library preparation and sequencin...

The activity of retroelements is one of the factors leading to genetic variability of the modern humans. Insertions of retroelements may result in alteration of gene expression and functional diversity between cells. In recent years an increasing amount of data indicating an elevated level of retroelements’ mobilisation in some human and animal tis...