Biology subjects

Trofimov, A.

Publications and source records attributed to Trofimov, A..

6 recordsLinked to original sources

bioRxiv2026

T-cell repertoire response in individuals with post-acute sequelae of COVID-19

T-cells are central to SARS-CoV-2 clearance and immunological memory, yet their contribution to the persistence of post-acute sequelae of COVID-19 (PASC) remains poorly understood. The immunological features that distinguish individuals who develop PASC from those who recover fully are unresolved, in part due to the phenotypic heterogeneity of the condition and the likely multiplicity of its underlying mechanisms. Here, we profiled longitudinal bulk TCR{beta} repertoires from 120 individuals in the INCOV cohort-71 with PASC and 49 without-sampled at two to three time points spanning the acute and post-acute phases of infection. Using robust statistical modeling of repertoire composition and clonal dynamics, we found that global statistics such as V, J gene usage and CDR3 length do not differ between groups, but that locally enriched sequence motifs and differentially dynamic clones reveal distinct T-cell signatures associated with PASC status. Clones contracting following the peak of the acute response were significantly enriched for SARS-CoV-2 specificity in both groups. Interestingly, Influenza A-specific TCRs were disproportionately enriched among contracting clones in PASC+ repertoires, implicating viral co-infection as a potential contributor to early disease severity and, possibly, PASC pathogenesis. Rare public TCR clones were markedly enriched for SARS-CoV-2 specificity, with PASC+ individuals harboring a modestly but significantly higher proportion than PASC- individuals. Together, we identified over 1,000 candidate TCR{beta} receptors potentially discriminating PASC+ from PASC- immune responses, opening a path toward the identification of disease-relevant T-cell specificities and the development of T-cell-based immunological biomarkers for long COVID.

immunology↗

bioRxiv2025

Genetic and environmental imprints on T cell receptor repertoires as predictors of graft-versus-host disease

AbstractHematopoietic cell transplantation (HCT) as potentially curative treatment for patients with hematologic malignancies relies on T cells to mediate the potentially curative graft-versus-tumor (GVT) effect, which may be associated with graft-versus-host disease (GVHD), a potentially life-threatening complication. T cells recognize peptides presented by Human Leukocyte Antigen (HLA) molecules. It is commonly believed that matching HLA alleles between donors and recipients ensures similarity in their T cell receptor (TCR) repertoires, thereby reducing the risk of GVHD and graft rejection. However, TCR repertoires are shaped by multiple factors beyond HLA genetics, including sex, age, and immune history. The extent to which genetic variation and past infections influence TCR repertoire composition and GVHD risk remains unclear. Here, we show that while HLA haplotypes contribute to broad TCR repertoire differences, recent viral infections significantly impact TCR composition and influence GVHD risk. Analyzing 401 patients who were uniformly transplanted from healthy HLA-identical sibling HCT donors, we introduced HLA-TCR coherence, a metric that quantifies the extent to which an individuals TCR repertoire reflects their HLA haplotype. We find that higher TCR-HLA coherence is associated with greater HLA heterozygosity and an increased incidence of severe acute GVHD (grade 3-4) in transplant recipients. Furthermore, in silico identification of virus-associated TCRs (vaTCRs) using TCR sequencing and viral serology reveal specific vaTCRs predictive of either increased or decreased GVHD risk. These findings suggest that beyond HLA allele matching, donor-specific immune history and repertoire characteristics are critical determinants of GVHD risk. Thus, a more systematic integration of donor immune history may offer a complementary avenue for refining donor selection and potentially improving transplant outcomes. One Sentence SummaryWhile genetics shape the potential of a donors T cell repertoire, factors like infections and HLA diversity influence its composition and impact on transplant outcomes, including GVHD risk.

immunology↗

bioRxiv2025

Cryptic leukemia antigens share homology with microbial epitopes and stimulate T-cell responses in healthy donors

Leukemia cells express cryptic tumor-specific antigens (TSAs) derived from aberrantly transcribed non-exomic genome sequences. These antigens are generally absent from healthy tissues yet shared across patients, making them attractive immunotherapy targets by minimizing on-target/off-tumor toxicity while offering broad applicability. However, their immunogenic potential and the nature of the T-cell repertoire they stimulate remain unknown. Cryptic antigen-specific CD8+ T cells could be expanded from healthy donor T-cell repertoires for six out of nine candidate acute leukemia cryptic TSA. T-cell receptor (TCR) and epitope sequence analysis revealed oligoclonal or near-monoclonal responses, involving shared and donor-restricted clonotypes recognizing cryptic TSAs which shared sequence homology with microbial epitopes. Orthotopic TCR replacement with cryptic TSA-specific TCR chains using a one-step CRISPR-Cas9 approach further validated the antigenic specificity and therapeutic potential of two TCRs respectively targeting cryptic TSAs from acute myeloid and lymphoid leukemia. To our knowledge, this is the first report describing functional TCRs directed against cryptic leukemia TSAs and highlights their potential as a new class of antigens for T-cell-based immunotherapies. Key pointsO_LIA high proportion of cryptic leukemia TSAs shares homology with microbial epitopes and can stimulate expansion of low-frequency T cell repertoire in healthy individuals. C_LIO_LIEx vivo expansion of cryptic TSA-specific T cells enables TCR identification that can be used to devise new T cell immunotherapies. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/691479v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1bd720dorg.highwire.dtl.DTLVardef@8ac6d6org.highwire.dtl.DTLVardef@104289aorg.highwire.dtl.DTLVardef@5a65e_HPS_FORMAT_FIGEXP M_FIG C_FIG ConclusionCryptic leukemia antigens elicit antigenic and specific T-cell responses and represents novel targets for TCR or BiTE immunotherapy.

immunology↗

bioRxiv2024

Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination

V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology---short stretches of sequence homology between gene ends---can bias the recombination process, the extent of microhomologys impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCR repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process. Significance StatementHumans rely on diverse adaptive immune receptor repertoires to effectively defend against infections. The receptor generation process, known as V(D)J recombination, is designed to create this diversity by stochastically joining V(D)J gene segments and modifying their junctions through nucleotide deletions and insertions. Previous studies, conducted in vitro, have suggested that short stretches of homologous nucleotides between gene segments can bias these recombination steps. In this study, we explore the extent to which these homologous nucleotides influence V(D)J recombination in humans using statistical inference on large-scale receptor repertoire sequencing data. Our findings reveal that microhomology significantly biases several recombination steps, with important practical implications for the analysis, processing, and interpretation of receptor sequences.

immunology↗

bioRxiv2023

Transposable elements regulate thymus development and function

Transposable elements (TE) are repetitive sequences representing [~]45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN LJ/{beta}. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

immunology↗

bioRxiv2022

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Based on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist throughout life, are highly shared among subjects, and are polyreactive to self and microbial antigens. Thus, >50% of cord blood TCRs are responsive to SARS-CoV2 and other common pathogens. TDT- dependent TCRs present distinct structural features and are less shared among subjects. TDT- dependent TCRs are produced in maximal numbers during infancy when thymic output and TDT activity reach a summit, are more abundant in subjects with AIRE mutations, and seem to play a dominant role in graft-versus-host disease. Factors decreasing thymic output (age, male sex) negatively impact TCR diversity. Males compensate for their lower repertoire diversity via hyperexpansion of selected TCR clonotypes.

immunology↗