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Deep exploration of the TCR CDR3β repertoire specific for viral CD4 T cell epitopes inside the circulating T cell repertoire

ABSTRACT: This study provides an in-depth analysis of the diversity of the CD4 TCR CDR3β repertoire specific to Influenza A (HA) and Epstein-Barr virus (EBNA) epitopes. Epitope-specific CD4 T cells from 13 healthy donors were enriched using a short-term culture step, isolated based on activation markers, and sequenced for their TCR CDR3β region using high-throughput sequencing. The frequency of each clonotype were then identified within the complete circulating CD4 T-cell CDR3β repertoire. For both epitopes, the clonotype distribution was markedly skewed, with a small number of highly expanded clones comprising approximately 60% of the repertoire, alongside numerous low-frequency clonotypes. VJ gene usage and motif preferences differed between the two peptides, highlighting epitope-specific TCR selectivity. The response was predominantly composed of private T-cell clonotypes. The proportion of public clonotypes can increase among donors sharing HLA class II molecules and reveals in HLA-unrelated donors the level of TCR promiscuity. Overall, our data demonstrate that CD4 T-cell responses to these viral epitopes are polyclonal and highly personalized. The modest overlap of clonotypes between donors, coupled with a long tail of low-frequency clones, suggests that the full diversity of the epitope-specific T-cell repertoire is likely broader than previously estimated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309566 | GEO | 2025/12/17

REPOSITORIES: GEO

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The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes

Project description:Non-mutated FVIII-specific CD4 T cell epitopes have been recently found to contribute to the development of inhibitors in patients with hemophilia A (HA), while auto-reactive CD4 T cells specific to FVIII circulate in the blood of healthy individuals at a frequency close to the foreign protein Ovalbumin. Thus, although FVIII is a self-protein, the central tolerance raised against FVIII appears to be low. In this study, we conducted a comprehensive analysis of the FVIII CD4 T cell repertoire in twenty-nine healthy donors. Sequencing of the CDR3β TCR region from isolated FVIII-specific CD4 T cells revealed a limited usage and pairing of TRBV and TRBJ genes, as well as a mostly hydrophobic composition of the CDR3β region according to their auto-reactivity. FVIII repertoire is dominated by a few clonotypes, with only 13 clonotypes accounting for half of the FVIII response. Through a large-scale epitope mapping of the full-length FVIII sequence, we identified 18 immunodominant epitopes located in the A1, A3, C1, and C2 domains and covering half of the T-cell response. These epitopes exhibited a broad specificity for HLA-DR or DP molecules or both. T-cell priming with this reduced set of peptides revealed that highly expanded clonotypes specific to these epitopes were responsible individually for up to 32% of the total FVIII repertoire. These FVIII T cell epitopes and clonotypes were shared among HLA-unrelated donors tested and previously reported HA patients. Our study highlights the role of the auto-reactive T cell response against FVIII in HA and its similarity to the response observed in healthy individuals. Thus, it provides valuable insights for the development of new tolerance induction and deimmunization strategies

2024-01-22 | GSE253521 | GEO

T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes

Project description:Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2×108 TCRB sequences of circulating naive, central memory, reg- ulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease.

2024-07-22 | GSE272431 | GEO

Longitudinal analysis of antigen-specific T cells after Shingrix vaccination

Project description:SHINGRIX vaccination was used to investigate the fate of antigen specific memory CD4+ T cell at both cellular and transcriptional level upon immunization in a one-year longitudinal study. SHINGRIX is a subunit vaccine with glycoprotein E (gE) of varicella zoster virus (VZV) as the immunogen and requires two doses at least 60 days apart for protection against Herpes Zoster in adults over 50 years old. Flow cytometry and single-cell RNA sequencing were used to evaluate cellular and transcriptomic changes of VZV gE epitope-specific CD4+ T cells in a TCR clonotypic fashion pre and post vaccination. Antigen-specific T cells remained at a higher frequency compared to baseline and retained markers of cell activation such as ICOS and PD1 even one year post-vaccination. Persistent TCR clonotypes amongst epitope-specific T-cells were common across different time points within each individual. Antigen-specific memory T cells with a dominant TCR clonotype at baseline remained at a relatively high frequency one year later after two doses of vaccine. In contrast, T cells with TCR clonotypes from naïve antigen specific cells at baseline could not be detected post-vaccination. Differential gene expression analyses of cells with identical TCR clonotypes show that cells post vaccination, including those at one year post vaccination, were distinct from cells at baseline, with upregulation of genes related to T cell differentiation, negative T cell regulation and T cell activation. Thus, in addition to an increase in frequency, committed memory T cells gain additional transcriptional changes upon vaccination that could alter the immune response against cognate immunogens compared to pre-vaccinated quiescent memory T cells.

2025-03-09 | GSE249632 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of T-cell clone)

Project description:Islet-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects are thought to be involved in disease pathogenesis, but full understanding of their role is complicated by their presence also in blood of in healthy subjects. To elucidate their role in T1D, we have combined flow cytometry and single cell RNA sequencing (RNA-seq) techniques to link prior antigen exposure, inferred from expanded TCR clonotypes, and functional capacities of islet antigen-reactive CD4+ memory T cells. We find that cells activated by pooled peptides from immunodominant islet antigens showed significantly higher clonotype sharing within recent onset T1D subjects than in healthy individuals, consistent with in vivo T cell expansion during disease progression. There was no clonotype sharing between donors, indicating a predominance of TCRs with distinct or “private” specificities. Expanded clonotypes could be stable, as one was detected at repeat visits by spanning more than a year by one subject. We identified distinct IGRP peptides as the targets of expanded TCR clonotypes from two T1D subjects, thereby implicating this molecule as a trigger for CD4+ T cell expansion during T1D. Transcriptome profiles of cells from T1D and healthy subjects differed, particularly in cells having the most highly expanded TCR clonotypes. As a group, cells with the most highly expanded TCR clonotypes showed Th2-like phenotypes, but at the single cell level there was phenotypic heterogeneity within and between donors. Our findings demonstrate unique specificities and phenotypes of individual islet-reactive CD4+ memory T cells that have expanded during disease progression.

2017-06-08 | GSE96562 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of CD4+ pooled islet antigen-reactive T cells)

2017-06-08 | GSE96568 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of CD8+ influenza-reactive T cells)

2017-06-08 | GSE96564 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (bulk RNA-seq of T-cell clone)

2017-06-08 | GSE96563 | GEO

Investigation of human peripheral T cells responsive to SARS-CoV-2 antigens

Project description:To elucidate the T cell epitopes of SARS-CoV-2, we stimulated human PBMCs from healthy donors and convalescent COVID-19 patients with various SARS-CoV-2 antigens, sorted the activated T cells and performed sc-RNA and -TCR sequencing. We obtained thousands of T cell clonotypes that responded to SARS-CoV-2 antigens, and identified the epitopes and restricting HLAs of several clonotypes that were significantly expanded in the COVID-19 patients.

2021-10-07 | GSE184806 | GEO

SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

Project description:During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire. SAP deficiency resulted in both a significant loss of an immatureGzma+Blk+Etv5+Tox2+γδT17 precursor population, and a significant increase inCd4+Cd8+Rorc+Ptcra+Rag1+thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data suggest that SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire.

2024-07-08 | GSE262064 | GEO

Human effector/memory CD4 T cell subsets: deep TCR profiling.

Project description:Clonal fate of helper T cells is governed by early costimulatory signals but may also depend on the mode of TCR interaction with peptide-MHC on APCs. We investigate TCR repertoires of eight effector/memory CD4+ T-cell subsets (Th1, Th2, nonclassical Th2 (Th2a), Th17, Th1-17, Tfh, Treg, Th22), revealing subset-specific physicochemical and recombinational features reproducible across donors. At a threshold of 3 reads per UMI, the number of obtained UMI-labeled cDNA molecules per repertoire per sample ranged from 5,300 to 303,500, and the number of CDR3 clonotype variants at the nucleotide level per repertoire per sample ranged from 1,200 to 83,200. Deep unbiased TCR profiling allowed us to assess the natural level of in vivo CD4+ subsets plasticity. We observed a major clonal exchange between Th17/Th22/Th2/Th2a and the high stability of Treg and Tfh subsets. The latter two subsets also show higher repertoire publicity across donors. Tfh repertoire features reflect those of mature antibodies and indicate stringent selection of highly antigen-specific, low cross-reactive TCRs. We conclude that functional subsets are marked with non-random universal for donors and specific features of passed selection. In future TCR sequencing applications, subset-specific profiling could provide better insights of normal and pathological states of adaptive immunity compared to the classical approach when TCR profiling is performed on bulk T cells or after rough division into CD4 and CD8-enriched populations.

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