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Blood Oct 2020Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is... (Review)
Review
Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is more common in adolescent and young adults and has a rapidly progressive clinical course and poor outcome due to its refractoriness to conventional chemotherapy regimens. Approximately 20% of the cases arise in the background of chronic immunosuppression or immune dysregulation. Patients commonly present with constitutional symptoms, hepatic and liver enlargement, and cytopenias; hematophagocytic syndrome can also occur. The most frequent chromosomal aberrations associated with HSTCL are isochromosome 7q and trisomy 8, and most cases harbor mutations in genes involved in chromatin modification or the JAK/STAT pathway. The rarity of this disease, along with lack of nodal involvement and presenting symptoms that mimic different entities including infectious etiologies, makes this lymphoma a significant diagnostic challenge. In this review, we highlight the clinical and pathologic features of HSTCL. Moreover, we summarize the results of recent molecular studies suggesting potential targets for novel therapeutics strategies.
Topics: Animals; Humans; Liver Neoplasms; Lymphoma, T-Cell; Splenic Neoplasms
PubMed: 32756940
DOI: 10.1182/blood.2019004118 -
Cellular & Molecular Immunology Sep 2020γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells... (Review)
Review
γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.
Topics: Animals; Humans; Immunotherapy; Ligands; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Neoplasms; Receptors, Antigen, T-Cell, gamma-delta
PubMed: 32699351
DOI: 10.1038/s41423-020-0504-x -
Cytometry. Part B, Clinical Cytometry May 2021Flow cytometric detection of T-cell clonality is challenging. The current available methodology for T-cell receptor (TCR) Vβ repertoire evaluation is a complex assay...
Flow cytometric evaluation of TRBC1 expression in tissue specimens and body fluids is a novel and specific method for assessment of T-cell clonality and diagnosis of T-cell neoplasms.
BACKGROUND
Flow cytometric detection of T-cell clonality is challenging. The current available methodology for T-cell receptor (TCR) Vβ repertoire evaluation is a complex assay and has limited sensitivity especially for detecting low levels of disease. Therefore, there is an unmet need for a reliable, simple, and rapid assay to identify T-cell clonality. The rearrangement of the TCRB gene involves the random and mutually exclusive expression of one of two constant β chain genes (TRBC1 and TRBC2), analogous to the kappa and lambda gene utilization by B cells.
METHODS
Here, we used a single TRBC1 antibody, in conjunction with other T-cell associated markers, to detect T-cell clonality in tissue biopsies and body fluids. A total of 143 tissue/body fluid specimens from 46 patients with a definitive diagnosis of a T-cell neoplasm and 97 patients with no T-cell malignancy were analyzed with a cocktail of monoclonal antibodies including CD2/CD3/CD4/CD5/CD7/CD8/CD45/TCRγδ/TRBC1.
RESULTS
We examined TRBC1 expression on neoplastic T-cell populations identified based on their immunophenotypic aberrancies, and monotypic TRBC1 expression was identified in all 46 known T-cell lymphoma cases. We applied a similar gating strategy to the 97 cases without T-cell neoplasms, and arbitrarily dissected T-cell populations into immunophenotypically distinct subsets; in this group, we found that all cases revealed an expected polytypic TRBC1 expression in all subsets.
CONCLUSIONS
Single TRBC1 antibody detection of T-cell clonality by flow cytometry is a simple, rapid, and robust assay that could be routinely utilized in flow cytometric laboratories.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Body Fluids; Female; Flow Cytometry; Humans; Immunophenotyping; Lymphoma, T-Cell; Male; Middle Aged; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes; Young Adult
PubMed: 32333725
DOI: 10.1002/cyto.b.21881 -
Proceedings of the National Academy of... Jun 2019γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important...
γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In -distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV and CMV donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.
Topics: Adult; Base Sequence; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Humans; Immunologic Memory; Killer Cells, Natural; Leukocytes, Mononuclear; Receptors, Antigen, T-Cell, gamma-delta; Sequence Analysis, RNA; T-Lymphocyte Subsets; Transcriptome
PubMed: 31118283
DOI: 10.1073/pnas.1818488116 -
Proceedings of the National Academy of... Jan 1993The generation of tumor-specific lymphocytes and their use in adoptive immunotherapy is limited to a few malignancies because most spontaneous tumors are very weak or...
Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors.
The generation of tumor-specific lymphocytes and their use in adoptive immunotherapy is limited to a few malignancies because most spontaneous tumors are very weak or not at all immunogenic. On the other hand, many anti-tumor antibodies have been described which bind tumor-associated antigens shared among tumors of the same histology. Combining the variable regions (Fv) of an antibody with the constant regions of the T-cell receptor (TCR) chains results in chimeric genes endowing T lymphocytes with antibody-type specificity, potentially allowing cellular adoptive immunotherapy against types of tumors not previously possible. To generalize and extend this approach to additional lymphocyte-activating molecules, we designed and constructed chimeric genes composed of a single-chain Fv domain (scFv) of an antibody linked with gamma or zeta chains, the common signal-transducing subunits of the immunoglobulin receptor and the TCR. Such chimeric genes containing the Fv region of an anti-trinitophenyl antibody could be expressed as functional surface receptors in a cytolytic T-cell hybridoma. They triggered interleukin 2 secretion upon encountering antigen and mediated non-major-histocompatibility-complex-restricted hapten-specific target cell lysis. Such chimeric receptors can be exploited to provide T cells and other effector lymphocytes, such as natural killer cells, with antibody-type recognition directly coupled to cellular activation.
Topics: Animals; Antigen-Antibody Reactions; Base Sequence; Binding Sites, Antibody; Genes, Immunoglobulin; Hybridomas; Immunoglobulin Fc Fragments; Interleukin-2; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Immunologic; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; Trinitrobenzenes
PubMed: 8421711
DOI: 10.1073/pnas.90.2.720 -
Genes Dec 2020The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger... (Comparative Study)
Comparative Study
The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αβ and γδ, which express distinct TR containing either α and β, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine () and the sheep () have recently been described and annotated by IMGT biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.
Topics: Adaptive Immunity; Animals; Cattle; Evolution, Molecular; Genes, T-Cell Receptor alpha; Genes, T-Cell Receptor delta; Genetic Loci; Molecular Sequence Annotation; Sheep, Domestic; Species Specificity
PubMed: 33379283
DOI: 10.3390/genes12010030 -
Frontiers in Immunology 2021In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids... (Comparative Study)
Comparative Study
In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (family ) include two key teleost species for aquaculture, rainbow trout () and Atlantic salmon ( which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified in , the majority with a close counterpart in . Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets.
Topics: Amino Acid Sequence; Animals; Conserved Sequence; Gene Expression Profiling; Gene Library; Genes, T-Cell Receptor; Genome; Models, Molecular; Molecular Sequence Annotation; Oncorhynchus mykiss; Phylogeny; Protein Conformation; RNA, Messenger; Receptors, Antigen, T-Cell; Salmo salar; Sequence Alignment; Sequence Homology, Amino Acid; Species Specificity; Terminology as Topic
PubMed: 34733285
DOI: 10.3389/fimmu.2021.753960 -
BMC Genomics Sep 2015In mammals, T cells develop along two discrete pathways characterized by expression of either the αβ or the γδ T cell receptors. Human and mouse display a low...
BACKGROUND
In mammals, T cells develop along two discrete pathways characterized by expression of either the αβ or the γδ T cell receptors. Human and mouse display a low peripheral blood γδ T cell percentage ("γδ low species") while sheep, bovine and pig accounts for a high proportion of γδ T lymphocytes ("γδ high species"). While the T cell receptor alpha (TRA) and delta (TRD) genes and the genomic organization of the TRA/TRD locus has been determined in human and mouse, this information is still poorly known in artiodactyl species, such as sheep.
RESULTS
The analysis of the current Ovis aries whole genome assembly, Oar_v3.1, revealed that, as in the other mammalian species, the sheep TRD locus is nested within the TRA locus. In the most 5' part the TRA/TRD locus contains TRAV genes which are intermingled with TRDV genes, then TRD genes which include seven TRDD, four TRDJ genes, one TRDC and a single TRDV gene with an inverted transcriptional orientation, and finally in the most 3' part, the TRA locus is completed by 61 TRAJ genes and one TRAC gene. Comparative sequence and analysis and annotation led to the identification of 66 TRAV genes assigned to 34 TRAV subgroups and 25 TRDV genes belonging to the TRDV1 subgroup, while one gene was found for each TRDV2, TRDV3 and TRDV4 subgroups. Multiple duplication events within several TRAV subgroups have generated the sheep TRAV germline repertoire, which is substantially larger than the human one. A significant proportion of these TRAV gene duplications seems to have occurred simultaneously with the amplification of the TRDV1 subgroup genes. This dynamic of expansion has also generated novel multigene subgroups, which are species-specific. Ovis aries TRA and TRD genes identified in this study were assigned IMGT definitive or temporary names and were approved by the IMGT/WHO-IUIS nomenclature committee. The completeness of the genome assembly in the 3' part of the locus has allowed us to interpret rearranged CDR3 of cDNA from both TRA and TRD chain repertoires. The involvement of one up to four TRDD genes into a single transcript makes the potential sheep TRD chain much larger than any known TR chain repertoire.
CONCLUSIONS
The sheep genome, as the bovine genome, contains a large and diverse repertoire of TRA and TRD genes when compared to the "γδ T cell low" species genomes. The composition and length of the rearranged CDR3 in TRD V-delta domains influence the three-dimensional configuration of the antigen-combining site thus suggesting that in ruminants, γδ T cells play a more important and specific role in immune recognition.
Topics: Animals; Cattle; Genome; Humans; Mice; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta
PubMed: 26383271
DOI: 10.1186/s12864-015-1790-z -
Direct regulation of TCR rearrangement and expression by E proteins during early T cell development.WIREs Mechanisms of Disease Nov 2022γδ T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and are an important early source of IL-17 in response to several pathogens. Like... (Review)
Review
γδ T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and are an important early source of IL-17 in response to several pathogens. Like αβ T cells, γδ T cells undergo a stepwise process of development in the thymus that requires recombination of genome-encoded segments to assemble mature T cell receptor (TCR) genes. This process is tightly controlled on multiple levels to enable TCR segment assembly while preventing the genomic instability inherent in the double-stranded DNA breaks that occur during this process. Each TCR locus has unique aspects in its structure and requirements, with different types of regulation before and after the αβ/γδ T cell fate choice. It has been known that Runx and Myb are critical transcriptional regulators of TCRγ and TCRδ expression, but the roles of E proteins in TCRγ and TCRδ regulation have been less well explored. Multiple lines of evidence show that E proteins are involved in TCR expression at many different levels, including the regulation of Rag recombinase gene expression and protein stability, induction of germline V segment expression, chromatin remodeling, and restriction of the fetal and adult γδTCR repertoires. Importantly, E proteins interact directly with the cis-regulatory elements of the TCRγ and TCRδ loci, controlling the predisposition of a cell to become an αβ T cell or a γδ T cell, even before the lineage-dictating TCR signaling events. This article is categorized under: Immune System Diseases > Stem Cells and Development Immune System Diseases > Genetics/Genomics/Epigenetics.
Topics: Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Thymus Gland; Cell Differentiation; Transcription Factors
PubMed: 35848146
DOI: 10.1002/wsbm.1578 -
Genes Apr 2021The role of γδ T cells in vertebrate immunity is still an unsolved puzzle. Species such as humans and mice display a low percentage of these T lymphocytes (i.e., "γδ...
The role of γδ T cells in vertebrate immunity is still an unsolved puzzle. Species such as humans and mice display a low percentage of these T lymphocytes (i.e., "γδ low species") with a restricted diversity of γδ T cell receptors (TR). Conversely, artiodactyl species (i.e., "γδ high species") account for a high proportion of γδ T cells with large γ and δ chain repertoires. The genomic organisation of the TR γ (TRG) and δ (TRD) loci has been determined in sheep and cattle, noting that a wide number of germline genes that encode for γ and δ chains characterise their genomes. Taking advantage of the current improved version of the genome assembly, we have investigated the genomic structure and gene content of the dromedary TRD locus, which, as in the other mammalian species, is nested within the TR α (TRA) genes. The most remarkable finding was the identification of a very limited number of variable germline genes (TRDV) compared to sheep and cattle, which supports our previous expression analyses for which the somatic hypermutation mechanism is able to enlarge and diversify the primary repertoire of dromedary δ chains. Furthermore, the comparison between genomic and expressed sequences reveals that genes, up to four incorporated in a transcript, greatly contribute to the increased diversity of the dromedary δ chain antigen binding-site.
Topics: Animals; Camelus; Computational Biology; Genetic Loci; Genome; Phylogeny; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta
PubMed: 33918850
DOI: 10.3390/genes12040544