αβ T-cell receptor bias in disease and therapy (Review)

Wang, Chunyan; Yu, Peifa; He, Xu; Fang, Yongxiang; Cheng, Wei-xia; Jing, Zhizhong

doi:10.3892/ijo.2016.3492

Cited by 14 publications

(10 citation statements)

References 93 publications

(84 reference statements)

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire

et al. 2019

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“…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.…”

Section: Intrathymic Aav8-zap-70 Transduction Promotes Long-term Mainmentioning

confidence: 99%

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Pouzolles

Machado

Guilbaud

et al. 2020

Journal of Allergy and Clinical Immunology

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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 zetaassociated 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 2/2 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 2/2 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.

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“…Based on this assumption, we attempted to identify CSFV-specific TCRs using the GeneScan spectratyping method. The degree of clonal proliferation and the functional status of T cells can be detected by monitoring the spectratypes, length or sequence of the CDR3 region of the TCR 27 . To the best of our knowledge, the present study is the first to describe the diversity and clonality of αβTCRs in CD4 + T cells from miniature pigs immunised with C-strain vaccine by immunoscope spectratyping.…”

Section: Discussionmentioning

confidence: 99%

“…In human’s TCR research, M. tuberculosis 38-kDa antigen-specific TCRs were screened and expressed in TCR-gene modified CD4 + and CD8 + T cells, antigen-specific secretion of cytokine and cytolytic activity were seen in TCR gene modified CD4 + and CD8 + T cells 33 . In addition, antigen-associated monoclonal TCR Vα and Vβ gene families can be incorporated into antitumor or antiviral disease therapy 27 , 34 . Two patients with CD8 + T cells which were genetically engineered to express the melanoma MART-1-restricted TCRα/β gene win 18 months life time without this disease 35 .…”

Section: Discussionmentioning

confidence: 99%

Monoclonal and oligoclonal TCR AV and BV gene usage in CD4+ T cells from pigs immunised with C-strain CSFV vaccine

Wang

Jia

et al. 2018

Sci Rep

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The classical swine fever virus C-strain vaccine (C-strain vaccine) plays a vital role in preventing and controlling the spread of classical swine fever (CSF). However, the protective mechanisms of C-strain vaccine and cellular immunity conferred by T cell receptors (TCRs) are less well defined. We aimed to analyse the association between the complementarity determining region 3 (CDR3) spectratype of αβTCR in CD4+ T cells and C-strain vaccine; and to find conserved CDR3 amino acid motifs in specific TCR α- and β-chains. We found that the CDR3 spectratype showed dynamic changes correlating with C-strain vaccine immunisation and that TCR AV5S/8–3S/8–4S/14/38 and BV4S/6S/7S/15S/30 gene families showed clonal expansion in immunised pigs. The sequences of CDR3 from these clonally expanded T cells indicated a high frequency of the ‘KLX’ motif in the TCR α chain and the ‘GGX’ motif in β chain, and Jα39, Jα43, Jβ2.5 and Jβ2.3 genes were also found in high frequency. To the best of our knowledge, this is the first report describing the dynamic changes of αβTCRs and conserved CDR3 amino acid motifs in CD4+ T cells from C-strain vaccine-immunised pigs, which will provide a basis for the development of high-efficiency epitope vaccines.

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αβ T-cell receptor bias in disease and therapy (Review)

Cited by 14 publications

References 93 publications

Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire

Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Monoclonal and oligoclonal TCR AV and BV gene usage in CD4+ T cells from pigs immunised with C-strain CSFV vaccine

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