Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire
François Van LaethemAnastasia N. TikhonovaLeonid A. PobezinskyXuguang TaiMotoko Y. KimuraCécile Le SaoutTerry I. GuinterAnthony J. AdamsSusan O. SharrowGünter BernhardtLionel FeigenbaumAlfred Singer
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Negative selection
MHC restriction
T cell receptor (TCR) is an integral part of T cell recognition antigen, and the sum of TCR of all T cells in an individual is called the TCR repertoire. Understanding the composition and characteristics of the TCR repertoire in healthy and pathological state helps us to gain an insight into adaptive immunity. At present, many analysis tools for high-throughput data have been developed, including basic composition analysis and downstream function analysis. The database of antigen-specific T cells established by researchers is fundamental to clinical research. The analysis of the functional characteristics of the TCR repertoire is critical to the understanding of TCR repertoire. However, the existing downstream analysis tools still requires further application and verification. This paper reviewed several commonly used TCR repertoire analysis tools, which hopefully can provide a reference for non-bioinformatics researchers in choosing analysis tools.
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Molecular analysis of T‐cell receptor (TCR) repertoire, by measuring the CDR3 heterogeneity length of beta‐variable regions (spectratyping), is useful for acquiring novel information on the status of immune system in primary immunodeficiency. Here, we evaluate TCR repertoire in a child with trichothiodystrophy (TTD) and combined immunodeficiency (CID). Spectratyping revealed marked alterations of TCR repertoire distribution: 21 and 10 out of 27 TCR Vβ (TCRBV) families and subfamilies were skewed in CD8 + and CD4 + subsets, respectively. These findings revealed, for the first time in a TTD patient with CID, a marked reduction in the TCR repertoire complexity, which may reflect alterations in the mechanisms regulating the generation and homeostasis of T cells.
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Negative selection
MHC restriction
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We previously demonstrated a central role for HLA genes in determining the T-cell receptor (TCR) repertoire. However, these studies also suggested that other genetic factors might also play a role in the development of this repertoire. In order to assess the role of non-HLA genes in the development of the TCR repertoire, we have analysed and compared the TCR repertoires of individuals in three families consisting of both monozygotic twins as well as an HLA-identical sib. TCR repertoire analysis was performed with both V-segment-specific MoAb and the polymerase chain reaction using TCRBV-segment-specific oligonucleotide primers. We observed that in every case the TCR repertoires of identical twins were more similar to each other than to their HLA-identical sib. Furthermore, in one family we were able to show by genotype analysis that most of the differences in repertoire between the identical twins and their HLA-identical sib were caused by polymorphisms in the TCR genes that influence expression levels. These studies document an important role for non-HLA genes in determining the TCR repertoire in man and raise the possibility that such TCR polymorphisms may play a significant role in determining disease susceptibility.
Immunogenetics
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Abstract T cell receptors (TCR) identify target cells presenting a ligand consisting of a major histocompatibility complex molecule (MHC) and an antigenic peptide. A considerable amount of evidence indicates that the TCR contacts both the peptide and the MHC components of the ligand. In fully differentiated T cells the interaction between the peptide and the TCR makes the critical contribution to eliciting a cellular response. However, during the positive selection of thymocytes the contribution of peptide relative to MHC is less well established. Indeed it has been suggested that the critical interaction for positive selection is between the TCR and the MHC molecule and that peptides can be viewed as either allowing or obstructing this contact. This predicts that a given TCR is capable of engaging multiple MHC/peptide complexes. In this study a system is described which detects simply engagement of the TCR by MHC/peptide complexes rather than the functional outcome of such interactions. Using this approach the extent to which peptides can influence contacts between the TCR and the MHC molecule has been examined. The results show that the TCR does in fact engage a wide range of ligands in an MHC‐restricted but largely peptide‐independent manner, suggesting that only a few peptides are able to prevent the TCR from contacting the MHC molecule.
MHC restriction
Negative selection
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We review recent data that increase our understanding of the ternary complex of the T cell receptor (TCR), antigenic peptides, and molecules of the major histocompatibility complex (MHC). Studies using synthetic peptide analogs for T-cell antigens have identified peptide residues that appear to interact with the MHC molecule and/or the TCR. The logical extension of these studies, using a complete replacement set of peptide analogues for a model peptide antigen, has more precisely defined the biochemical character of putative MHC and TCR contact residues, and indicated that the TCR is highly sensitive to subtle changes in peptide conformation. Insight into the binding site for peptide on the TCR has recently come from variant peptide immunization of TCR single-chain transgenic mice. These experiments indicate that residues encoded by the V(D)J junctions of both TCR chains contact peptide directly. TCR-MHC contacts have also been studied, using in vitro-mutagenized MHC molecules, particularly those altered at residues predicted to point "up," toward the TCR. These studies reveal that TCR-MHC contacts appear to be quite flexible, and vary between even closely related TCRs. A measure of the affinity of TCR for peptide/MHC complexes has come from competition experiments using soluble MHC complexed with specific peptides. This affinity, with a KD of 5 x 10(-5) M, is several orders of magnitude lower than that of most antibodies for their protein antigens and suggests that the sequence of events leading to T-cell activation begins with antigen-independent adhesion.
MHC restriction
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The interaction between T-cell receptors (TCRs) and major histocompatibility complex (MHC)-bound epitopes is one of the most important processes in the adaptive human immune response. Several hypotheses on TCR triggering have been proposed. Many of them involve structural and dynamical adjustments in the TCR/peptide/MHC interface. Molecular Dynamics (MD) simulations are a computational technique that is used to investigate structural dynamics at atomic resolution. Such simulations are used to improve understanding of signalling on a structural level. Here we review how MD simulations of the TCR/peptide/MHC complex have given insight into immune system reactions not achievable with current experimental methods. Firstly, we summarize methods of TCR/peptide/MHC complex modelling and TCR/peptide/MHC MD trajectory analysis methods. Then we classify recently published simulations into categories and give an overview of approaches and results. We show that current studies do not come to the same conclusions about TCR/peptide/MHC interactions. This discrepancy might be caused by too small sample sizes or intrinsic differences between each interaction process. As computational power increases future studies will be able to and should have larger sample sizes, longer runtimes and additional parts of the immunological synapse included.
Immunological synapse
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Abstract Background Analyzing the T-cell receptor (TCR) repertoire is important with the advent of precision medicine and immunotherapy, as TCR repertoire could serve as a biomarker of immune response and disease progression. Though many TCR analysis methods have been developed for analyzing various aspects of the TCR repertoire, the usage of these methods requires experience in bioinformatics and is technically cumbersome. There is an urgent need to develop an easy-used online server for TCR repertoire analysis. Methods TCR CDR3 sequence with clinical information were collected from TCRdb. In TCR repertoire general analysis, Renyi entropy and 1-Pielou’s index was used to calculate diversity and clonality of the TCR repertoire, respectively. GIANA and iGraph were used to discover possible disease-specific TCR CDR3 sequences and construct a TCR network in network analysis. OLGA was used to calculate the generation probability of a CDR3 sequence in healthy individuals in public analysis. PHATE was used to embed TCR repertoire in embedding analysis. Results In this study, we introduce TCRosetta, a powerful platform for analyzing and annotating TCR repertoire. Above 244 million complementary determining region 3 (CDR3) sequences of TCR beta chain (TRB) with disease information are integrated into the webserver, enabling big-data-based CDR3 annotation for the first time. The main functions of TCRosetta are as follows: (i) General feature analysis for TCR repertoire, including diversity, V/J gene usage, CDR3 length distribution, and clonality etc.; (ii) Annotate the disease preference of TCR repertoire and TRB CDR3 sequences; (iii) TCR repertoire network construction and analysis; (iv) Calculate generation probability of TRB CDR3 sequences. TCRosetta is the first comprehensive online server for TCR repertoire analysis and is useful for immunology research.
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Negative selection
Positive selection
Gene rearrangement
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