TTFields treatment effects on newly diagnosed Glioblastoma patients in peripheral T lymphocytes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193729 | GEO | 2022/04/20
REPOSITORIES: GEO
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Project description:<p>Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-specific CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly among different individuals. A genetic influence was seen for the sharing of individual TCR sequences from antigen-specific cells, but not for repertoire richness or the selection of clonal dominance. VZV vaccination favored the expansion of infrequent VZV-specific TCRs including those from naïve T cells while leaving dominant T cell clones mostly unaffected.</p>
| phs001082 | dbGaP
Project description:Purpose: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that clonal expansion of CD4+ T cell in response to cardiac neoantigens promote the progression of HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger HF and profiled the TCR repertoire by mRNA sequencing of CD4+ T cells from 3 pooled Nur77GFP reporter mice, which transiently express GFP upon TCR engagement. We performed TCR clonal analysis of 5000 TCR-activated GFP+CD4+ T cells sorted from the LV, and 5000 CD4+ T cells sorted from the thymus, the inguinal lymph nodes (iLNs) and the heart-draining mediastinal lymph nodes (mLNs) by bulk RNA sequencing of the TCR beta chain after 8wks of TAC surgery. Paired‐end 300 base pair reads were obtained by Illumina sequencing and aligned and assembled using MiXCR software. Results: As expected, the greatest number of unique TCR beta clonotypes (4412 clones) – and therefore the highest TCR diversity – was identified in the thymus. The heart draining mLNs showed a much lower degree of TCR clonal diversity relative to the peripheral iLNs, suggesting that cardiac antigen-driven clonal expansion occurs at the mLNs that directly drain the heart. TCR-activated GFP+CD4+ T cells in the LV represented even lower TCR diversity relative to other sites. Conclusion: Collectively, our study demonstrates that in response to cardiac pressure overload, CD4+ T cells clonally expand in the heart-draining mLN; whilst a limited repertoire of CD4+ T cell clones engage endogenous antigens in the heart.
2020-11-11 | GSE161172 | GEO
Project description:Infiltrating T-lymphocytes from the peripheral blood into the central nervous system (CNS) play a dynamic role in the development of a neurological immune-mediated diseases. HAM/TSP is a chronic progressive inflammatory neurological disorder associated with human T-cell lymphotropic virus type I (HTLV-I) infection. In this chronic myelopathy, virus-infected circulating T-cells infiltrate the CNS and an immune response is initiated against the components of CNS. As the HTLV-I proviral load (PVL) has been used as the best clinical marker for patient diagnostic with HAM/TSP, we hypothesized there might be a signature on T-cell receptor (TCR) clonal repertoire in these patients, which could distinguish HAM/TSP patients from the healthy population, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease as multiple sclerosis (MS). With this in mind, we applied an innovative unbiased molecular technique – unique molecular identifier (UMI) library-strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). To address whether the clonal expansion correlates with the patient’s PVL level, analysis of longitudinal TCR repertoire was performed in 2 HAM/TSP patients. Over 5.6 million TCR sequences were generated per sample on HiSeq 2500 Illumina system and analyzed through the molecular identifier groups-based error correction pipeline (MiGEC). Bioinformatic analysis showed that clones with more than 8 reads had a lower coefficient of variation (CV) and then could be used with confidence to evaluate the TCR clonal expansion. While HAM/TSP patients showed the higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subject’s group. In addition, correlation of the PVL with TCR clonal expansion was observed in HAM/TSP patients at longitudinal time-points. Surprisingly, MS patients showed a higher diversity of TCR repertoire along with a very slight clonal T-cell expansion in comparison to either HAM/TSP patients or HC. Despite of the higher TCR clonal expansion in HAM/TSP patients, a non-shared or “private” TCR repertoire was observed in these patients. No clones that shared the same CDR3 amino acid sequences were seen in HC and MS patients. However, a cluster of related CDR3 amino acid sequences were observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. It suggestes that a TCR-repertoire signature might characterize patients with MS. Our findings suggest that even though a unique TCR-b repertoire shapes the immune response in patients with neurological immune-mediated disease, a relatedness on clonal T-cell repertoire exist in MS.
2019-01-29 | GSE121082 | GEO
Project description:CD4+ regulatory T cells (Tregs) activate and expand in response to many different types of injuries, suggesting that they play a critical role in controlling the host response to tissue damage. Here we use multi-dimensional profiling techniques to comprehensively characterize injury responsive Tregs in mice. CD44high Tregs expand in response to injury and are more suppressive than CD44low Tregs. T cell receptor (TCR) analysis reveal that CD44high Tregs undergo TCRαβ clonal expansion and increased CDR3 diversity in response to injury. Bulk and single-cell RNA sequencing with paired TCR clonotype analysis demonstrate that important Treg-associated genes were significantly differentially expressed in both CD44high and CD44low Tregs with expanded TCR clonotypes. CyTOF analysis verified protein expression of these genes on CD44high Tregs, with increases in Helios, Galectin-3 and PYCARD expression following injury. Collectively, these data provide new insights into CD44high Tregs, an important subset in the response to injury to tissue damage.
2022-05-01 | GSE174789 | GEO
Project description:CD4+ regulatory T cells (Tregs) activate and expand in response to many different types of injuries, suggesting that they play a critical role in controlling the host response to tissue damage. Here we use multi-dimensional profiling techniques to comprehensively characterize injury responsive Tregs in mice. CD44high Tregs expand in response to injury and are more suppressive than CD44low Tregs. T cell receptor (TCR) analysis reveal that CD44high Tregs undergo TCRαβ clonal expansion and increased CDR3 diversity in response to injury. Bulk and single-cell RNA sequencing with paired TCR clonotype analysis demonstrate that important Treg-associated genes were significantly differentially expressed in both CD44high and CD44low Tregs with expanded TCR clonotypes. CyTOF analysis verified protein expression of these genes on CD44high Tregs, with increases in Helios, Galectin-3 and PYCARD expression following injury. Collectively, these data provide new insights into CD44high Tregs, an important subset in the response to injury to tissue damage.
2022-05-01 | GSE174788 | GEO
Project description:Collectively, these data present evidence that the antitumor response mediated by CD8a ALN-1 correlates with clonal expansion and increased TCR repertoire diversity in the TDLN and the tumor tissue, implying epitope spreading.
2021-11-12 | GSE188583 | GEO
Project description:T cells primarily drive the autoimmune destruction of pancreatic beta cells in Type 1 diabetes (T1D). However, the profound yet uncharacterized diversity of the T cell populations in vivo has hindered obtaining a clear picture of the T cell changes that occur longitudinally as T1D onset happens. Here we profiled the transcriptome and TCR repertoire of T cells at single-cell resolution from longitudinally collected peripheral blood and islets of Non-Obese Diabetic (NOD) mice using single-cell RNA sequencing technology. We detected clonal expansion and characterized the transcriptional landscape of "islets-matching" T cell clones in the blood and "blood-matching" T cell clones in islets of diabetic NOD mice using the TCR as a molecular barcode. The clonally matching cells show enriched interferon-gamma response pathways than non-matching cells in blood and islets. In addition, we identified a set of transcriptional markers associated with the matching status of the T cell clones. This study provides a single-cell level transcriptome and TCR repertoire atlas of T cells in NOD mice. The results show that TCR and transcriptional signature can be used combinedly to develop biomarker panels for tracking and investigating islets infiltrating T cells.
2024-10-31 | GSE200695 | GEO
Project description:Single cell TCR sequencing was performed to examine the clonal type changes in cord blood derived gamma-delta T-cells following in-vitro expansion in a co-culture with EBV-LCL feeder over 2 weeks. Following 2 weeks of expansion, the cells were challenged with the AML cell line K562. Single-cell TCR was performed after 24 hours post-challenge to identify clones that were preferentially expanded, as well as the corresponding cell states mapped using single-cell RNA-sequencing.
2023-09-08 | GSE214287 | GEO
Project description:Background and methods: T-cell large granular lymphocytosis (T-LGL) is a lymphoproliferative disease usually presenting with cytopenia, and typically characterized by clonal expansion of terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs). Conventional methods including flow cytometry and sequencing of Vb chains provided incomplete signature of TCR repertoire. Efforts to characterize transcriptome of clonal CTLs using whole peripheral blood or after enrichment of specific clones by flow cytometry have not provided satisfying resolution and scale due to heterogeneity among individual patients. We applied single cell TCR-sequencing coupled with single cell RNA sequencing to CD3+ T cells from a relatively large cohort (N=13) of T-LGL patients in a clinical protocol to prospectively test therapy with alemtuzumab in refractory disease, to characterize TCR repertoire and to define pathophysiologic mechanism at the single cell level, and to determine mechanisms of response and non-response to therapy. Results: T cells have less clonal diversity in T-LGL patients, compared with that in healthy donors. TCR repertoires in T-LGLL follow power law distribution but at a larger scale. There are no significant evidence of common TCR clonotypes among T-LGLL patients. TCR usage and T cell activation states shape T cell phenotypes. Cell survival and apoptosis gene programs are deregulated in T-LGL. Immunosuppressive treatment modulates clonality and gene expression in T-LGL. Conclusion: Our work complements and adds to previous modeling of T cell clonal expansion. Single cell sequencing of transcriptomes supports a theory of fluctuation in clone fitness, antigenic and environmental factors in concert with clone-specific and cell-specific germline and somatic genetic factors (HLA and STAT3).
2021-11-22 | GSE168859 | GEO
Project description:Clonal expansion is a hallmark of adaptive immunity, and appears to be driven by high antigen-specific receptor avidity as shown by research using murine in vivo models. In humans, however, the functionality of antigen-specific T cell clonotypes that are recruited into primary and recall immune responses remains surprisingly elusive. In this regard, the vaccination program during the SARS-CoV-2 pandemic represented a unique research opportunity by provision of highly standardized cohorts of healthy human individuals receiving immunizations against a previously unseen antigen. Here, we analyzed 30 HLA-typed individuals before, short-term and long-term after three mRNA vaccinations against SARS-CoV-2. We performed an in-depth characterization of the magnitude, phenotype, clonal composition and functionality of antigen-specific CD8 T cell responses by ELISPOT, flow cytometry and single-cell RNA sequencing, including CITE seq of 130 surface antigens and 16 T cell epitope specificities. 89 T cell receptors (TCRs) covering three complete epitope-specific repertoires were re-expressed by CRISPR/Cas9-mediated orthotopic TCR replacement and tested for their avidity. TCR repertoires underwent continuous tailoring, with high TCR avidity being linked to both clonal persistence and expansion. However, epitope-specific repertoires also maintained diversity by concomitant contraction and new emergence of functional T cell clones over time. These data on the phenotype and clonal selection within human antigen-specific T cell responses instruct our understanding of human T cell biology and may guide the development of enhanced or novel vaccines.
2024-10-31 | GSE261967 | GEO