scholarly journals TheαβTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site

2020 ◽  
Vol 117 (35) ◽  
pp. 21336-21345 ◽  
Author(s):  
Wonmuk Hwang ◽  
Robert J. Mallis ◽  
Matthew J. Lang ◽  
Ellis L. Reinherz
Keyword(s):  
T Cell ◽  
Cellular Response ◽  
Complex Molecule ◽  
Immune Surveillance ◽  
Major Histocompatibility Complex Molecule ◽  
Contact Dynamics ◽  
Fine Tuning ◽  
Dynamics Simulation ◽  
Cell Repertoire ◽  
Catch Bond

EachαβT cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCRαβligand-binding heterodimer and the noncovalently associated CD3 signaling subunits. When bound by ligand, an antigenic peptide arrayed by a major histocompatibility complex molecule (pMHC), the TCRαβhas a longer bond lifetime under piconewton-level loads. The atomistic mechanism of this “catch bond” behavior is unknown. Here, we perform molecular dynamics simulation of a TCRαβ-pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCRαβdomain allostery. The TCRαβ-pMHC interface is dynamically maintained by contacts with a spectrum of occupancies, introducing a level of control via relative motion between Vα and Vβ variable domains containing the pMHC-binding complementarity-determining region (CDR) loops. Without adequate load, the interfacial contacts are unstable, whereas applying sufficient load suppresses Vα-Vβ motion, stabilizing the interface. A second level of control is exerted by Cα and Cβ constant domains, especially Cβ and its protruding FG-loop, that create mismatching interfaces among the four TCRαβdomains and with a pMHC ligand. Applied load enhances fit through deformation of the TCRαβmolecule. Thus, the catch bond involves the entire TCRαβconformation, interdomain motion, and interfacial contact dynamics, collectively. This multilayered architecture of the machinery fosters fine-tuning of cellular response to load and pMHC recognition. Since the germline-derived TCRαβectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverseαβTCRs constituting the T cell repertoire.

scholarly journals Recent advances in T-cell engineering for use in immunotherapy

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2344 ◽  
Author(s):  
Preeti Sharma ◽  
David M. Kranz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Single Chain ◽  
Cell Therapies ◽  
Recent Advances

Adoptive T-cell therapies have shown exceptional promise in the treatment of cancer, especially B-cell malignancies. Two distinct strategies have been used to redirect the activity of ex vivo engineered T cells. In one case, the well-known ability of the T-cell receptor (TCR) to recognize a specific peptide bound to a major histocompatibility complex molecule has been exploited by introducing a TCR against a cancer-associated peptide/human leukocyte antigen complex. In the other strategy, synthetic constructs called chimeric antigen receptors (CARs) that contain antibody variable domains (single-chain fragments variable) and signaling domains have been introduced into T cells. Whereas many reviews have described these two approaches, this review focuses on a few recent advances of significant interest. The early success of CARs has been followed by questions about optimal configurations of these synthetic constructs, especially for efficacy against solid tumors. Among the many features that are important, the dimensions and stoichiometries of CAR/antigen complexes at the synapse have recently begun to be appreciated. In TCR-mediated approaches, recent evidence that mutated peptides (neoantigens) serve as targets for endogenous T-cell responses suggests that these neoantigens may also provide new opportunities for adoptive T-cell therapies with TCRs.

scholarly journals Obesity accelerates thymic aging

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3803-3812 ◽  
Author(s):  
Hyunwon Yang ◽  
Yun-Hee Youm ◽  
Bolormaa Vandanmagsar ◽  
Jennifer Rood ◽  
K. Ganesh Kumar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Surveillance ◽  
Cell Receptor ◽  
Effector Memory ◽  
Thymic Involution ◽  
Cell Repertoire ◽  
Diet Induced Obesity ◽  
Age Related ◽  
Repertoire Diversity

Abstract As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.

scholarly journals In a small multideterminant peptide, each determinant is recognized by a different V beta gene segment.

1992 ◽  
Vol 176 (1) ◽  
pp. 297-302 ◽  
Author(s):  
N K Nanda ◽  
K K Arzoo ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Segment ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Sperm Whale ◽  
Cell Receptor ◽  
T Cell Response ◽  
Absolute Requirement ◽  
Beta Gene

Given the vast potential for diversification of the T cell receptor (TCR) repertoire and the fact that V(a) beta mice exist in the wild, it would have been predicted that in spite of the absence of 10 TCR V beta gene segments, V(a) beta mice would still have been able to produce an antigen-specific T cell response to all determinants. We have recently shown that Vb beta mice, with a wild-type TCR V beta repertoire, respond to peptide 110-121 of sperm whale myoglobin, with a majority of T cells expressing TCR V beta 8.2 and restricted to a hybrid I-A(d)/I-E(d) major histocompatibility complex molecule, and a smaller number of T cells expressing TCR V beta 8.1 and restricted to the I-A(d) molecule. However, V(a) beta mice, lacking members of the TCR V beta 8 gene family, responded only with I-A(d)-restricted T cells. Thus, it appeared that the I-A(d)-restricted response was less constrained, or more plastic. We now show that the two separate panels of I-A(d)-restricted T cell hybrids derived from V(a) beta or Vb beta mice in fact recognize distinct determinants within the same peptide 110-121. The determinant recognized by V(a) beta T cells is NH2 terminal (core: 110-118) with an absolute requirement for the residue Ala-110 for a successful interaction with TCRs. On the other hand, Vb beta T cells recognize the COOH-terminal region (core: 112-118) on the same peptide with an absolute requirement for COOH-terminal residue 118. In the dominance hierarchy displayed by the three distinct determinants of peptide 110-121, V(a) beta mice cannot recognize the two most dominant: the hybrid I-A(d)/I-E(d)-restricted determinant and the COOH-terminal, I-A(d)-restricted determinant. They instead respond with T cells specific for a third, distinctly NH2-terminal determinant. Our results show a strict association between recognition of a particular specificity and TCR V beta usage. This evidence suggests that even when a small peptide induces a heterogenous group of TCR V beta S, this need not be considered evidence for plasticity. Rather, at the level of individual determinants within the peptide, the results can point in the opposite direction, towards serious constraints in recognition at the level of V beta expression.

scholarly journals RNA m6A demethylase ALKBH5 regulates the development of γδ T cells

2020 ◽  
Author(s):  
Richard Flavell ◽  
Chenbo Ding ◽  
Zhibin Yu ◽  
Hao Xu ◽  
Manolis Roulis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Target Genes ◽  
Immune Surveillance ◽  
Γδ T Cells ◽  
Rna Modification ◽  
Γδ T Cell ◽  
Cell Repertoire

Abstract γδ T cells are abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells origin in thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common post-transcriptional modifications of mRNA in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here we show that depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal S. typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.

Transgenic mice to study T-cell receptor gene regulation and repertoire formation

Genome ◽  
1989 ◽  
Vol 31 (2) ◽  
pp. 652-655 ◽  
Author(s):  
Michael Steinmetz ◽  
Horst Blüthmann ◽  
Stefan Ryser ◽  
Yasushi Uematsu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
Target Cells ◽  
Allelic Exclusion

Transgenic mice have been obtained with genes coding for an αβ T-cell receptor that recognizes the male-specific antigen H-Y in association with the Db class I major histocompatibility complex molecule. Most if not all of the T-cells express the β chain encoded by the transgene and show allelic exclusion of endogenous β genes. In contrast, the expression of the α transgene does not completely block rearrangement and formation of functional endogenous α genes. In H-2b transgenic female mice the transgenic T-cell receptor is functionally expressed on at least 30% of CD8+ peripheral T-lymphocytes as indicated by their ability to lyse male target cells. Also in transgenic H-2b male mice a large proportion of peripheral T-cells appear to express the transgenic receptor. However, these cells do not react with male target cells because they show only low level or no expression of CD8 cell interaction molecules. Tolerance is established in the male transgenic thymus through deletion of CD4+CD8+ immature thymocytes.Key words: transgenic mice, immune system, T-lymphocytes, T-cell receptor, tolerance, CD8 surface antigen, enhancer, gene rearrangement, allelic exclusion.

scholarly journals Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Martin S. Davey ◽  
Carrie R. Willcox ◽  
Stephen P. Joyce ◽  
Kristin Ladell ◽  
Sofya A. Kasatskaya ◽  
...  
Keyword(s):  
T Cell ◽  
Clonal Selection ◽  
Immune Surveillance ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Adaptive Immune

scholarly journals Evidence of T cell receptor β-chain patterns in inflammatory and noninflammatory bowel disease states

1999 ◽  
Vol 276 (3) ◽  
pp. G613-G621 ◽  
Author(s):  
Lawrence J. Saubermann ◽  
Christopher S. J. Probert ◽  
Andreas D. Christ ◽  
Andreas Chott ◽  
Jerrold R. Turner ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Bowel Disease ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Intestinal Lymphocytes ◽  
Β Chain

T cell activation, as defined by expression of relevant cell surface molecules, such as the interleukin-2 receptor (CD25), is increased in many chronic relapsing diseases, including inflammatory bowel disease (IBD). These T cells are generally activated through contact of their clonotypic T cell receptor (TCR) with a peptide antigen presented by a major histocompatibility complex molecule. One of the putative antigenic contact sites for the TCR is the third complementarity determining region (CDR3) of the TCR β-chain variable region (TCRBV). Therefore, analysis of the TCRBV CDR3 provides insight into the diversity of antigens encountered by a given T cell population. This study evaluated the TCRBV CDR3 usage of the activated intestinal lymphocytes from human subjects with IBD, diverticulitis (inflammatory control), and a normal tissue control. Public patterns, as demonstrated by shared TCRBV CDR3 amino acid sequences of activated intestinal T cell subpopulations, were observed. In particular, a public pattern of TCRBV22, a conserved valine in the fifth position, and use of TCRBJ2S1 or TCRBJ2S5 was present in three of four Crohn’s disease subjects while not present in the ulcerative colitis subjects. However, the private patterns of TCRBV CDR3 region amino acid sequences were far more striking and easily demonstrated in all individuals studied, including a normal noninflammatory control. Thus we conclude that selective antigenic pressures are prevalent among an individual’s activated intestinal lymphocytes.

Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior antitumor activity and higher TCR functional avidity

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2131-2139 ◽  
Author(s):  
Susanne Wilde ◽  
Daniel Sommermeyer ◽  
Bernhard Frankenberger ◽  
Matthias Schiemann ◽  
Slavoljub Milosevic ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Complex Molecule ◽  
Major Histocompatibility Complex Molecule ◽  
Major Histocompatibility ◽  
Functional Avidity ◽  
Histocompatibility Complex ◽  
Tumor Associated Antigen

Abstract Adoptive transfer of T cells expressing transgenic T-cell receptors (TCRs) with antitumor function is a hopeful new therapy for patients with advanced tumors; however, there is a critical bottleneck in identifying high-affinity TCR specificities needed to treat different malignancies. We have developed a strategy using autologous dendritic cells cotransfected with RNA encoding an allogeneic major histocompatibility complex molecule and a tumor-associated antigen to obtain allo-restricted peptide-specific T cells having superior capacity to recognize tumor cells and higher functional avidity. This approach provides maximum flexibility because any major histocompatibility complex molecule and any tumor-associated antigen can be combined in the dendritic cells used for priming of autologous T cells. TCRs of allo-restricted T cells, when expressed as transgenes in activated peripheral blood lymphocytes, transferred superior function compared with self-restricted TCR. This approach allows high-avidity T cells and TCR specific for tumor-associated self-peptides to be easily obtained for direct adoptive T-cell therapy or for isolation of therapeutic transgenic TCR sequences.

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