scholarly journals Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1471 ◽  
Author(s):  
Katie Healy ◽  
Anna Pasetto ◽  
Michał J. Sobkowiak ◽  
Chai Fen Soon ◽  
Markus Cornberg ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Hepatitis ◽  
Clinical Success ◽  
Therapeutic Option ◽  
Cell Receptor ◽  
Lessons Learned ◽  
Antiviral Responses ◽  
Cell Immunity ◽  
Gene Technologies ◽  
Safety Considerations

Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.

scholarly journals PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kaitao Li ◽  
Zhou Yuan ◽  
Jintian Lyu ◽  
Eunseon Ahn ◽  
Simon J. Davis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Success ◽  
Clinical Intervention ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Antigen Recognition ◽  
Inhibitory Function ◽  
Src Homology

AbstractDespite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1’s targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR–pMHC–CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1’s potent inhibitory function and its value as a target for clinical intervention.

scholarly journals Age-Related Immune Profile of the T Cell Receptor Repertoire, Thymic Recent Output Function, and miRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yan Xu ◽  
Ling Xu ◽  
Cunte Chen ◽  
Yikai Zhang ◽  
Chengwu Zeng ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Sharp Decrease ◽  
Cell Receptor ◽  
Cell Immune Response ◽  
Immune Senescence ◽  
Receptor Repertoire ◽  
Age Related ◽  
Cell Immunity ◽  
Group I

Background. T cell immunity plays a central role in the body’s defense system, including maintaining homeostasis and preventing tumorigenesis and viral infection. Immune system functions degenerate with age, leading to immune senescence. Physiologically, immune senescence is characterized by a decrease in T cell receptor diversity, naive T cell deficiency, and alterations in T cell immune-related miRNAs. However, little is known about the characteristics of T cell immunosenescence in Chinese individuals. Results. A significant decrease in the miR-17, miR-92a, and miR-181a levels in PBMCs was detected with age. The miR-92a and miR-181a levels were upregulated in CBMCs when comparing healthy individuals to group I (0~9 years), whereas miR-17 was downregulated. The sjTREC level in PBMCs was negatively correlated with age, and a sharp decrease in sjTRECs was found between groups I and II (10~19 years). Twenty-four TCR Vβ subfamilies could be detected in most samples, and most displayed polyclonality, while skewed expression of the Vβ subfamilies as well as an increased oligoclonal tendency was found with age. Similarly, the frequencies of the TCR Vγ and Vδ subfamilies decreased with age, and the alteration in clonality appeared to be stable at different ages. Conclusion. We made the novel observation of T cell immunosenescence with age in Chinese individuals, which may provide information for immune targets to enhance the T cell immune response in immunotherapy settings for elderly patients.

scholarly journals Direct evidence for new T-cell generation by patients after either T-cell–depleted or unmodified allogeneic hematopoietic stem cell transplantations

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2235-2242 ◽  
Author(s):  
Sharon R. Lewin ◽  
Glenn Heller ◽  
Linqi Zhang ◽  
Elaine Rodrigues ◽  
Eva Skulsky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Opportunistic Infections ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
The Difference ◽  
T Cell Phenotypes

Abstract Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P = .02). Recipients of T-cell–depleted allografts initially had lower TRECs than unmodified allograft recipients (P < .01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P < .01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA+ T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P < .01). Recipients of all ages of either unmodified or T-cell–depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell–depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell– depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.

T-cell receptor transfer for boosting HIV-1-specific T-cell immunity in HIV-1-infected patients

AIDS ◽  
2016 ◽  
Vol 30 (14) ◽  
pp. 2149-2158 ◽  
Author(s):  
Christiane Mummert ◽  
Christian Hofmann ◽  
Angela G. Hückelhoven ◽  
Silke Bergmann ◽  
Sandra M. Mueller-Schmucker ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Hiv 1

Regulation of T-cell migration by co-stimulatory molecules

2007 ◽  
Vol 35 (5) ◽  
pp. 1114-1118 ◽  
Author(s):  
R. David ◽  
F.M. Marelli-Berg
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
T Cell Receptor ◽  
Antigenic Site ◽  
Cell Receptor ◽  
T Cell Immunity ◽  
T Cell Migration ◽  
Cell Immunity ◽  
Essential Contribution

Migration of primed T-cells to the antigenic site is an essential event in the development of effective immunity. This process is tightly regulated in order to ensure efficient and specific responses. Most studies have focused on non-specific mediators of T-cell migration, including integrins and chemokines. However, recent studies have highlighted the key role of the T-cell receptor and co-stimulatory molecules in guiding T-cell access to antigenic tissue. Here, we review the experimental evidence for an essential contribution of co-stimulation-mediated molecular interactions regulating T-cell migration in the development of T-cell immunity and tolerance.

scholarly journals Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3096-3103 ◽  
Author(s):  
Kenrick Semple ◽  
Antony Nguyen ◽  
Yu Yu ◽  
Honglin Wang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Specific Protein ◽  
Cell Immunity ◽  
Cd28 Costimulation

Abstract CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naive CD4 T cells (CD25−Foxp3−) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2–inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.

scholarly journals A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands

2018 ◽  
Vol 3 (28) ◽  
pp. eaar3947 ◽  
Author(s):  
Pouya Faridi ◽  
Chen Li ◽  
Sri H. Ramarathinam ◽  
Julian P. Vivian ◽  
Patricia T. Illing ◽  
...  
Keyword(s):  
T Cell ◽  
Posttranslational Modifications ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Peptide Fragments ◽  
Leukocyte Antigen ◽  
Cell Immunity ◽  
Probable Outcome ◽  
Hla Binding ◽  
Cis And Trans

The diversity of peptides displayed by class I human leukocyte antigen (HLA) plays an essential role in T cell immunity. The peptide repertoire is extended by various posttranslational modifications, including proteasomal splicing of peptide fragments from distinct regions of an antigen to form nongenomically templated cis-spliced sequences. Previously, it has been suggested that a fraction of the immunopeptidome constitutes such cis-spliced peptides; however, because of computational limitations, it has not been possible to assess whether trans-spliced peptides (i.e., the fusion of peptide segments from distinct antigens) are also bound and presented by HLA molecules, and if so, in what proportion. Here, we have developed and applied a bioinformatic workflow and demonstrated that trans-spliced peptides are presented by HLA-I, and their abundance challenges current models of proteasomal splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA-binding sequence features and are as frequently identified as cis-spliced peptides found bound to a number of different HLA-A and HLA-B allotypes. Structural analysis reveals that the junction between spliced peptides is highly solvent exposed and likely to participate in T cell receptor interactions. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design, and immunotherapy.

scholarly journals Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia

2017 ◽  
Vol 7 (3) ◽  
pp. e1405204 ◽  
Author(s):  
Takero Shindo ◽  
Kazutaka Kitaura ◽  
Hiroshi Ureshino ◽  
Kazuharu Kamachi ◽  
Masaharu Miyahara ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Deep Sequencing ◽  
Cell Receptor ◽  
T Cell Immunity ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cell Immunity

scholarly journals The GPR171 pathway suppresses T cell activation and limits antitumor immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuki Fujiwara ◽  
Robert J. Torphy ◽  
Yi Sun ◽  
Emily N. Miller ◽  
Felix Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
T Cell Immunity ◽  
Antigen Stimulation ◽  
Cell Immunity

AbstractThe recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

scholarly journals IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

2011 ◽  
Vol 208 (12) ◽  
pp. 2545-2560 ◽  
Author(s):  
Hye-Ran Kim ◽  
Byeong-Hun Jeon ◽  
Hyun-Su Lee ◽  
Sin-Hyeog Im ◽  
Masatake Araki ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Transmembrane Domain ◽  
Cell Receptor ◽  
Immunoglobulin Superfamily ◽  
Tcr Signaling ◽  
Cell Functions ◽  
Cell Immunity

Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8+ T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell–APC interaction.

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