Figure 1 - uploaded by Xiaobing He
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Examples of human TCR gene rearrangement, forming the functional gene encoding the αβ heterodimer on the surface of T cells. (A) V-J recombination of the TCR-α chain DNA. The α-chain DNA (in which the TCR-δ locus is also embedded), similar to the light-chain (L-chain) DNA of immunoglobulin, undergoes V-J recombination, brings together one of 46 TRAV segments and one of 51 TRAJ segments. The TCR-α transcript produced where V, J and C segments connect directly after the intron sequences are spliced out. (B) Heterodimer structure of αβ-TCR on the surface of T lymphocytes. (C) V-D-J recombination of the TCR-β chain DNA. The β-chain DNA is analogous to the heavy chain (H-chain) DNA of immunoglobulin, undergoes two-step recombination: first Dβ to Jβ and then Vβ to Dβ-Jβ rearrangement. The intervening sequences are then cut off, generating the TCR-β chain transcript with V, D, J and C region adjacent. The leader sequence is removed from the nascent peptide chain. TCR, T cell receptor.
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The diversity and specificity of T cell receptors (TCR), the characteristics of T-cell surface marker, are central to the adaptive immunity. TCR variability is required for successful immunization coverage because this structural foundation is indispensable for the valid identification of short antigen peptides (derived from degraded antigens) that...
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... β and δ chains, which feature an additional D (diversity) region (9). The re-arrange- ment of V (D) and J through recombination signal sequences (RSS) and the formation of a functional antigen receptor via the activity of the lymphoid-specific protein recombination activating gene (RAG) 1 and RAG 2 exclusively occurs during thymocyte development (Fig. 1). This process involves the random re-arrangement of various V and J genes at the TCR-α locus and V, D and J genes at the TCR-β locus during T-cell development, additional diversity is produced by the random insertion or deletion of >20 non-germline nucleotides at region junctions (V-(N)-J, V-(N)-D and/or D-(N)-J; N represents ...
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T cells are primed in secondary lymphoid organs by establishing stable interactions with antigen-presenting cells (APCs). However, the cellular mechanisms underlying the termination of T cell priming and the initiation of clonal expansion remain largely unknown. Using intravital imaging, we observed that T cells typically divide without being assoc...
Citations
... The diversity and specificity of T cell receptors (TCR) are the core of adaptive immunity [29]. TCR variability is necessary for the effective identification of antigen peptides that are presented by the MHC molecules on the surface of antigen-presenting cells [29]. ...
... The diversity and specificity of T cell receptors (TCR) are the core of adaptive immunity [29]. TCR variability is necessary for the effective identification of antigen peptides that are presented by the MHC molecules on the surface of antigen-presenting cells [29]. To date, numerous examples of TCR bias have been observed in various diseases [30][31][32][33][34]. ...
T-cell receptor (TCR) is crucial in T cell-mediated virus clearance. To date, TCR bias has been observed in various diseases. However, studies on the TCR repertoire of COVID-19 patients are lacking. Here, we used single-cell V(D)J sequencing to conduct comparative analyses of TCR repertoire between 12 COVID-19 patients and 6 healthy controls, as well as other virus-infected samples. We observed distinct T cell clonal expansion in COVID-19. Further analysis of VJ gene combination revealed 6 VJ pairs significantly increased, while 139 pairs significantly decreased in COVID-19 patients. When considering the VJ combination of α and β chains at the same time, the combination with the highest frequency on COVID-19 was TRAV12-2-J27-TRBV7-9-J2-3. Besides, preferential usage of V and J gene segments was also observed in samples infected by different viruses. Our study provides novel insights on TCR in COVID-19, which contribute to our understanding of the immune response induced by SARS-CoV-2.
... The HLA-B7 EBV RPPspecific TCR repertoire in our cohort demonstrated remarkable bias toward the use of TRBV4-1 and TRAV38-1. Such biased TCR usage appears to be a general phenomenon of repertoires specific for immunodominant epitopes from persistent viral infections (64). ...
... Skewing of the TCR repertoire is often observed in response to persistent viral infections including HIV/SIV, EBV, CMV, and influenza virus (64), with this feature suggested to result from the prior selection of T cells with high-affinity TCRs (37). In accordance, our study has unveiled a shared TRBV4-1 TCR bias that dominates the EBV RPP -specific CD8 + T cell response among unrelated HLA-B7 + individuals. ...
EBV is one of the most common viruses found in humans and is prototypic of a persistent viral infection characterized by periods of latency. Across many HLA class I molecules, the latent-specific CD8+ T cell response is focused on epitopes derived from the EBNA-3 protein family. In the case of HLA-B*07:02 restriction, a highly frequent class I allele, the T cell response is dominated by an epitope spanning residues 379-387 of EBNA-3 (RPPIFIRRL [EBVRPP]). However, little is known about either the TCR repertoire specific for this epitope or the molecular basis for this observed immunodominance. The EBVRPP CD8+ T cell response was common among both EBV-seropositive HLA-B*07:02+ healthy and immunocompromised individuals. Similar TCRs were identified in EBVRPP-specific CD8+ T cell repertoires across multiple HLA-B7+ individuals, indicating a shared Ag-driven bias in TCR usage. In particular, TRBV4-1 and TRAV38 usage was observed in five out of six individuals studied. In this study, we report the crystal structure of a TRBV4-1+ TCR-HLA-B*07:02/EBVRPP complex, which provides a molecular basis for the observed TRBV4-1 bias. These findings enhance our understanding of the CD8+ T cell response toward a common EBV determinant in HLA-B*07:02+ individuals.
... 34 Furthermore, infections and tumors can drive an antigen-mediated bias in ab TCR repertoires. 88 Although only a few studies have monitored TCR repertoires in patients or mice treated with rAAV vectors, the robust T-cell response against an AAV transgene in one trial was shown to be associated with a biased TCRBV repertoire. 89 Therefore it was important to assess the repertoire diversity in our gene-corrected mice. ...
Background:
Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes.
Objective:
We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zeta-associated protein of 70 kDa (ZAP-70)-deficient murine model.
Methods:
AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70-/- mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated.
Results:
AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8-ZAP-70 vector into ZAP-70-/- mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected.
Conclusions:
Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function.
... Recently, biased αβTCR repertoires and TCR "signatures" raised against specific antigens have been observed in various diseases, especially in virus infections, autoimmune disorders, and tumor (10). Little is known about whether, and if so how MHC genotype influences the composition of TCR repertoire. ...
T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the “net” genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR β chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.
... 33 In the present study, we, therefore, addressed whether neoantigenreactive T cells are present in peripheral blood and/or TME of HNSCC patients and whether these cells can be activated and expanded from PBMCs using cognate neoantigen peptides for stimulation. 22,34,35 We further examined whether TCRs of these in vitro-stimulated T cells were included in TILs of corresponding patients. Among the 15 peptides that we selected for in vitrostimulation of neoantigen-specific T cells, only one led to the isolation of a functional TCR targeting a mutation identified in the HNSCC patient A6 (MAGOHB G17A ). ...
To develop a practically applicable method for T-cell receptor (TCR)-engineered T cell immunotherapy targeting neoantigens, we have been attempting to identify neoantigen-specific T cell receptors (TCRs) and establish TCR-engineered T cells in a 3–4-month period. In this study, we report the characterization of T cell repertoires in tumor microenvironment (TME) and identification of neoantigen-specific TCRs after stimulation of patient-derived T cells. We screened 15 potential neoantigen peptides and successfully identified two CD8⁺HLA-dextramer⁺ T cells, which recognized MAGOHBG17A and ZCCHC14P368L. All three dominant TCR clonotypes from MAGOHBG17A-HLA dextramer-sorted CD8⁺ T cells were also found in T cells in TME, while none of dominant TCR clonotypes from ZCCHC14P368L-HLA dextramer-sorted CD8⁺ T cells was found in the corresponding TME. The most dominant TCRA/TCRB pairs for these two neoantigens were cloned into HLA-matched healthy donors’ T lymphocytes to generate TCR-engineered T cells. The functional assay showed MAGOHBG17A TCR-engineered T cells could be significantly activated in a mutation-specific, HLA-restricted and peptide-dose-dependent manner while ZCCHC14P368L TCR-engineered T cells could not. Our data showed neoantigen-reactive T cell clonotypes that were identified in the patient’s peripheral blood could be present in the corresponding TME and might be good TCRs targeting neoantigens.
Introduction
An association between functional dyspepsia (FD) and wheat-containing foods has been reported in observational studies, however, an adaptive response has not been demonstrated. We examined whether antigens present in wheat could provoke a response from FD duodenal lymphocytes.
Methods
Lamina propria mononuclear cells (LPMCs) were isolated from duodenal biopsies from 50 FD patients and 23 controls. LPMCs were exposed to gluten (0.2mg/mL) or gliadin (0.2mg/mL) for 24 hours. Flow cytometry was performed to phenotype lymphocytes. qPCR was used to measure expression of gliadin-associated T-cell receptor alpha variant ( TRAV)26-2.
Results
In response to gliadin (but not gluten) stimulation, the effector Th2-like population was increased in FD LPMCs compared to controls and unstimulated FD LPMCs. Duodenal gene expression of TRAV26- 2 was decreased in FD compared to controls. We identified a positive association between gene expression of this T cell receptor variant and LPMC effector Th17-like cell populations in FD patients, but not controls following exposure to gluten, but not gliadin.
Conclusion
Our findings suggest that gliadin exposure provokes a duodenal effector Th2-like response in FD patients, supporting the notion that food antigens drive responses in some patients. Further, these findings suggest that altered lymphocyte responses to wheat proteins play a role in FD pathogenesis.
Introduction Bacillus Calmette–Guérin (BCG)-vaccination affords variable protection against tuberculosis (TB), which is unexplained. The project hypothesises that there is inter-individual variation in both the naïve T cell (NTC) response to a standard stimulation and in the ‘trained’ immune response of BCG-vaccine-primed T cells on secondary exposure to antigen and that relationships exist between the two. The aim of the study is to identify factors by which T cell vaccine design may be improved. Methods Blood was collected from 107 adults immediately prior to BCG-vaccination. NTCs were enriched from pre-BCG frozen/thawed peripheral blood mononuclear cells (PBMC), subjected to anti-CD3/CD28 stimulation and then characterised by fluorescence-activated cell-sorting (FACS) on markers of activation, differentiation and proliferation. Participants were then re-bled eight weeks later and their frozen/thawed PBMC incubated with purified protein derivative (PPD) in three separate assays before FACS to measure activation induced markers, Th1 cytokines and proliferation. A DNA sequencing pipeline and computational analysis were employed to examine 67 participants’ peripheral blood TCR repertoires in response to BCG. Results There was inter-individual variation amongst all pre-vaccination NTC stimulation assay parameters, some of which were strongly positively correlated. In the post-BCG-vaccination assays, all parameters were significantly upregulated in response to incubation with PPD and demonstrated wide ranges of inter-individual variation. In both sets of assays, results were found to be reproducible and inter-individual variation surpassed technical noise. Post-BCG expanded TCRs generated clusters of homologous sequences, were shared between multiple participants and shared homology with annotated TB-specific TCRs. Discussion There is inter-individual variation in multiple parameters to standard NTC stimulation, possibly reflecting intrinsic variance in the T cell intracellular signalling capacity. BCG has variable T cell immunogenicity, which may bear relation to pre-vaccination parameters. BCG-vaccination induces a polyclonal population of T cells with the ability to recognise mycobacterial antigens. Improved understanding of the T cell component to variable BCG vaccine efficacy may aid next generation TB vaccine development.
Although T cell receptors (TCRs) are related to the progression of breast cancer (BC), but their prognostic values remain unclear. We downloaded the mRNA profiles and corresponding clinical information of 1413 BC patients from the Cancer Genome Atlas and Gene Expression Omnibus database, respectively. The different expression analysis of 104 TCRs in BC samples was performed, and the consensus clustering based on 104 TCRs was performed by using the K‐mean method of R language. Univariate cox regression analysis was used to screen TCRs significantly associated with the prognosis of BC, and LASSO Cox analysis was applied to optimize key TCRs. Risk Score was calculated using the prognostic model constructed based on six optimal TCRs, and Multivariate Cox regression analysis was used to determine whether it was as an independent prognostic signature. Finally, the nomogram was constructed by to predict the overall survival of BC patients. Six optimal TCRs (ZAP70, GRAP2, NFKBIE, IFNG, NFKBIA and PAK5) which were favorable for prognosis of BC patients were screened. Risk score could reliably predict the prognosis of BC patients as an independent prognostic signature. In addition, when bringing into two independent prognostic signatures age and risk score, the nomogram model could better predict the overall survival of BC patients. Our results suggested that the poor prognosis of BC patients with high risk might be due to immunosuppressive microenvironment. In summary, a risk prognostic model based on six TCRs was established and could efficiently predict the prognosis of BC patients.
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