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Current Opinion in Pulmonary Medicine Sep 2020Sarcoidosis is a systemic disease characterized by granulomatous inflammation of unknown cause. There is extensive heterogeneity between patients with respect to the... (Review)
Review
PURPOSE OF REVIEW
Sarcoidosis is a systemic disease characterized by granulomatous inflammation of unknown cause. There is extensive heterogeneity between patients with respect to the number and types of organs involved, disease course, and response to therapy. Recent research in the field has leveraged 'omics' techniques such as transcriptomics to identify important 'molecular profiles' in the disease. These tools may help in identifying clinically useful biomarkers and targets for therapy.
RECENT FINDINGS
Several studies have used gene expression profiling of predesignated lists or the entire genome to find genes and markers that differentiate sarcoidosis from healthy controls, but only a few have compared sarcoidosis patients based on disease phenotypes and organ involvement. The common gene pathways that have been repeatedly identified include those related to the interferon response, T-cell receptor signaling, and the major histocompatibility complex.
SUMMARY
While the molecular profiling studies to date offer the ability to compare sarcoidosis and health as well as across tissues, further longitudinal studies that include sarcoidosis patients with varying outcomes with respect to organ involvement and response to treatment are needed to identify clinically important phenotypes in the disease that can then be differentiated based on molecular features.
Topics: Biomarkers; Disease Progression; Gene Expression Profiling; Gene Regulatory Networks; Genomics; Humans; Interferon-gamma; Metabolomics; MicroRNAs; Microbiota; Phenotype; Proteomics; Receptors, Antigen, T-Cell; Sarcoidosis; Signal Transduction; T-Lymphocytes
PubMed: 32701678
DOI: 10.1097/MCP.0000000000000716 -
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 Jun 2020T lymphocytes are the principal actors of vertebrates' cell-mediated immunity. Like B cells, they can recognize an unlimited number of foreign molecules through their... (Review)
Review
T lymphocytes are the principal actors of vertebrates' cell-mediated immunity. Like B cells, they can recognize an unlimited number of foreign molecules through their antigen-specific heterodimer receptors (TRs), which consist of αβ or γδ chains. The diversity of the TRs is mainly due to the unique organization of the genes encoding the α, β, γ, and δ chains. For each chain, multi-gene families are arranged in a TR locus, and their expression is guaranteed by the somatic recombination process. A great plasticity of the gene organization within the TR loci exists among species. Marked structural differences affect the TR γ (TRG) locus. The recent sequencing of multiple whole genome provides an opportunity to examine the TR gene repertoire in a systematic and consistent fashion. In this review, we report the most recent findings on the genomic organization of TRG loci in mammalian species in order to show differences and similarities. The comparison revealed remarkable diversification of both the genomic organization and gene repertoire across species, but also unexpected evolutionary conservation, which highlights the important role of the T cells in the immune response.
Topics: Adaptive Immunity; Amino Acid Sequence; Animals; Evolution, Molecular; Genome; Genomics; Humans; Mammals; Phylogeny; Receptors, Antigen, T-Cell
PubMed: 32517024
DOI: 10.3390/genes11060624 -
Journal of Clinical Immunology Jan 2023Patients with Wiskott-Aldrich syndrome (WAS) harbor mutations in the WAS gene and suffer from immunodeficiency, microthrombocytopenia, and eczema. T-cells play an...
Patients with Wiskott-Aldrich syndrome (WAS) harbor mutations in the WAS gene and suffer from immunodeficiency, microthrombocytopenia, and eczema. T-cells play an important role in immune response in the skin and the γδT-cells have an important role in skin homeostasis. Since WAS patients often present with eczema, we wanted to examine whether the T-cell receptor gamma (TRG) repertoire of the γδT-cells is affected in these patients. In addition, the immunoglobulin heavy chain (IGH) repertoire from genomic DNA of WAS patients was not yet studied. Thus, we sought to determine the effects that specific WAS mutations from our patients have in shaping the TRG and IGH immune repertoires. We collected clinical and genetic data on four WAS patients, each harboring a different mutation in the WAS gene. Using next-generation sequencing (NGS), we analyzed their TRG and IGH repertoires using genomic DNA isolated from their peripheral blood. We analyzed the TRG and IGH repertoire sequences to show repertoire restriction, clonal expansions, preferential utilization of specific V genes, and unique characteristics of the antigen binding region in WAS patients with eczema compared to healthy controls. Both the TRG and IGH repertoire showed diverse repertoire comparable to healthy controls on one the hand, and on the other hand, the IGH repertoire showed increased diversity, more evenly distributed repertoire and immaturity of the antigen binding region. Thus, we demonstrate by analyzing the repertoire based on genomic DNA, the various effect that WAS mutations have in shaping the TRG and IGH adaptive immune repertoires.
Topics: Humans; Wiskott-Aldrich Syndrome; Immunoglobulin Heavy Chains; B-Lymphocytes; T-Lymphocytes; Eczema
PubMed: 36044170
DOI: 10.1007/s10875-022-01349-8 -
Frontiers in Immunology 2021T-cell antigen receptors (TRs) in vertebrates can be divided into αβ or γδ, encoded by TRA/D, TRG, or TRB loci. TRs play a central role in mammal cellular immunity,...
T-cell antigen receptors (TRs) in vertebrates can be divided into αβ or γδ, encoded by TRA/D, TRG, or TRB loci. TRs play a central role in mammal cellular immunity, which occurs by rearrangement of V, D, J, and C genes in the loci. The bat is the only mammal with flying ability and is considered the main host of zoonotic viruses, an important public health concern. However, at present, little is known about the composition of bat TR genes. Based on the whole genome sequence of the greater horseshoe bat () and referring to the TR/IG annotation rules formulated by the international ImMunoGeneTics information system (IMGT), we present a complete annotation of TRA/D, TRG, and TRB loci of . A total of 128 V segments, three D segments, 85 J segments, and 6 C segments were annotated and compared with other known mammalian data. The characteristics of the TR locus and germline genes of are analyzed.
Topics: Animals; Biological Evolution; Cats; Cattle; Chiroptera; Computational Biology; Genetic Loci; Humans; Immunogenetics; Mice; Molecular Sequence Annotation; Phylogeny; Rabbits; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Sequence Alignment; T-Lymphocytes; Whole Genome Sequencing
PubMed: 34659234
DOI: 10.3389/fimmu.2021.741408 -
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 -
BMC Genomics Aug 2016The bottlenose dolphin (Tursiops truncatus) is a mammal that belongs to the Cetartiodactyla and have lived in marine ecosystems for nearly 60 millions years. Despite its...
Genomic and expression analyses of Tursiops truncatus T cell receptor gamma (TRG) and alpha/delta (TRA/TRD) loci reveal a similar basic public γδ repertoire in dolphin and human.
BACKGROUND
The bottlenose dolphin (Tursiops truncatus) is a mammal that belongs to the Cetartiodactyla and have lived in marine ecosystems for nearly 60 millions years. Despite its popularity, our knowledge about its adaptive immunity and evolution is very limited. Furthermore, nothing is known about the genomics and evolution of dolphin antigen receptor immunity.
RESULTS
Here we report a evolutionary and expression study of Tursiops truncatus T cell receptor gamma (TRG) and alpha/delta (TRA/TRD) genes. We have identified in silico the TRG and TRA/TRD genes and analyzed the relevant mature transcripts in blood and in skin from four subjects. The dolphin TRG locus is the smallest and simplest of all mammalian loci as yet studied. It shows a genomic organization comprising two variable (V1 and V2), three joining (J1, J2 and J3) and a single constant (C), genes. Despite the fragmented nature of the genome assemblies, we deduced the TRA/TRD locus organization, with the recent TRDV1 subgroup genes duplications, as it is expected in artiodactyls. Expression analysis from blood of a subject allowed us to assign unambiguously eight TRAV genes to those annotated in the genomic sequence and to twelve new genes, belonging to five different subgroups. All transcripts were productive and no relevant biases towards TRAV-J rearrangements are observed. Blood and skin from four unrelated subjects expression data provide evidence for an unusual ratio of productive/unproductive transcripts which arise from the TRG V-J gene rearrangement and for a "public" gamma delta TR repertoire. The productive cDNA sequences, shared both in the same and in different individuals, include biases of the TRGV1 and TRGJ2 genes. The high frequency of TRGV1-J2/TRDV1- D1-J4 productive rearrangements in dolphins may represent an interesting oligo-clonal population comparable to that found in human with the TRGV9- JP/TRDV2-D-J T cells and in primates.
CONCLUSIONS
Although the features of the TRG and TRA/TRD loci organization reflect those of the so far examined artiodactyls, genomic results highlight in dolphin an unusually simple TRG locus. The cDNA analysis reveal productive TRA/TRD transcripts and unusual ratios of productive/unproductive TRG transcripts. Comparing multiple different individuals, evidence is found for a "public" gamma delta TCR repertoire thus suggesting that in dolphins as in human the gamma delta TCR repertoire is accompanied by selection for public gamma chain.
Topics: Amino Acid Sequence; Animals; Bottle-Nosed Dolphin; Gene Expression Profiling; Gene Expression Regulation; Genetic Loci; Humans; Molecular Sequence Data; Phylogeny; Protein Structure, Secondary; RNA; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Sequence Alignment; Skin
PubMed: 27528257
DOI: 10.1186/s12864-016-2841-9 -
Current Opinion in Immunology Apr 2009The four T cell receptor genes (Tcra, Tcrb, Tcrg, Tcrd) are assembled by V(D)J recombination according to distinct programs during intrathymic T cell development. These... (Review)
Review
The four T cell receptor genes (Tcra, Tcrb, Tcrg, Tcrd) are assembled by V(D)J recombination according to distinct programs during intrathymic T cell development. These programs depend on genetic factors, including gene segment order and recombination signal sequences. They also depend on epigenetic factors. Regulated changes in chromatin structure, directed by enhancers and promoter, can modify the availability of recombination signal sequences to the RAG recombinase. Regulated changes in locus conformation may control the synapsis of distant recombination signal sequences, and regulated changes in subnuclear positioning may influence locus recombination events by unknown mechanisms. Together these influences may explain the ordered activation and inactivation of T cell receptor locus recombination events and the phenomenon of Tcrb allelic exclusion.
Topics: Animals; Gene Rearrangement, T-Lymphocyte; Humans; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Recombination, Genetic; Signal Transduction; VDJ Exons; VDJ Recombinases
PubMed: 19362456
DOI: 10.1016/j.coi.2009.03.009 -
Immunity Mar 2023Human T cell receptors (TCRs) are critical for mediating immune responses to pathogens and tumors and regulating self-antigen recognition. Yet, variations in the genes...
Human T cell receptors (TCRs) are critical for mediating immune responses to pathogens and tumors and regulating self-antigen recognition. Yet, variations in the genes encoding TCRs remain insufficiently defined. Detailed analysis of expressed TCR alpha, beta, gamma, and delta genes in 45 donors from four human populations-African, East Asian, South Asian, and European-revealed 175 additional TCR variable and junctional alleles. Most of these contained coding changes and were present at widely differing frequencies in the populations, a finding confirmed using DNA samples from the 1000 Genomes Project. Importantly, we identified three Neanderthal-derived, introgressed TCR regions including a highly divergent TRGV4 variant, which mediated altered butyrophilin-like molecule 3 (BTNL3) ligand reactivity and was frequent in all modern Eurasian population groups. Our results demonstrate remarkable variation in TCR genes in both individuals and populations, providing a strong incentive for including allelic variation in studies of TCR function in human biology.
Topics: Humans; Receptors, Antigen, T-Cell; Antigens; Genes, T-Cell Receptor
PubMed: 36796364
DOI: 10.1016/j.immuni.2023.01.026 -
BMC Genomics Sep 2020Goats (Capra hircus), one of the first domesticated species, are economically important for milk and meat production, and their broad geographical distribution reflects...
BACKGROUND
Goats (Capra hircus), one of the first domesticated species, are economically important for milk and meat production, and their broad geographical distribution reflects their successful adaptation to diverse environmental conditions. Despite the relevance of this species, the genetic research on the goat traits is limited compared to other domestic species. Thanks to the latest goat reference genomic sequence (ARS1), which is considered to be one of the most continuous assemblies in livestock, we deduced the genomic structure of the T cell receptor beta (TRB) and gamma (TRG) loci in this ruminant species.
RESULTS
Our analyses revealed that although the organization of the goat TRB locus is broadly similar to that of the other artiodactyl species, with three in-tandem D-J-C clusters located at the 3' end, a complex and extensive series of duplications have occurred in the V genes at the 5' end, leading to a marked expansion in the number of the TRBV genes. This phenomenon appears to be a feature of the ruminant lineage since similar gene expansions have also occurred in sheep and cattle. Likewise, the general organization of the goat TRG genes is typical of ruminant species studied so far, with two paralogous TRG loci, TRG1 and TRG2, located in two distinct and distant positions on the same chromosome as result of a split in the ancestral locus. Each TRG locus consists of reiterated V-J-J-C cassettes, with the goat TRG2 containing an additional cassette relative to the corresponding sheep and cattle loci.
CONCLUSIONS
Taken together, these findings demonstrate that strong evolutionary pressures in the ruminant lineage have selected for the development of enlarged sets of TRB and TRG genes that contribute to a diverse T cell receptor repertoire. However, differences observed among the goat, sheep and cattle TRB and TRG genes indicate that distinct evolutionary histories, with independent expansions and/or contractions, have also affected each ruminant species.
Topics: Animals; Evolution, Molecular; Gene Dosage; Genes, T-Cell Receptor beta; Genes, T-Cell Receptor gamma; Goats; Phylogeny
PubMed: 32912163
DOI: 10.1186/s12864-020-07022-x