scholarly journals T-Cell Receptor Clustering Methods Used for Single Cell Analysis: Potential Application in Oncology

2021 ◽  
pp. 1-5
Author(s):  
Jason Paul Buttigieg ◽  
Jason Paul Buttigieg ◽  
Kristian Helmerson ◽  
Brendon Coventry
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Immune Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Cell Types ◽  
Current Evidence ◽  
Receptor Clustering ◽  
Cell Receptors

We know that T-cell activation and effector function is integral for cancer cell destruction in immunotherapeutic treatment in oncology. The fundamental behaviour of T-cells at the time of activation is poorly understood but is likely to be central to this action. Cellular clustering occurs on at least two levels: gathering of multiple mobile cells of similar type, and aggregation between different cell types. Receptors are implicated in both of these processes. Analysis of receptor clustering is a different process whereby receptors form clusters on the cell membrane surface and can be studied to determine their relationship to immune activation. Receptor clustering has been shown to occur in some (perhaps all) cell types, but little is known about this phenomenon, particularly in T-lymphocytes. T-Cell Receptors (TCRs) which are important for the activation of T-lymphocytes. T-cell receptors, also known as cluster of differentiation 3 (CD3) molecules, bind specific antigen to create intracellular signaling in the process of T-cell activation as part of the immune response. The detail of how TCRs physically behave on the T-lymphocyte surface and specifically how they cluster remains unclear, including during the early phases of initiation of immune activation in the T-cell response. The aim of this review is to investigate how receptor clustering that has been studied, can be more effectively studied in the future and what the current evidence suggests about TCR clustering/T-cell activity relationships.

scholarly journals Superresolution imaging reveals nanometer- and micrometer-scale spatial distributions of T-cell receptors in lymph nodes

2016 ◽  
Vol 113 (26) ◽  
pp. 7201-7206 ◽  
Author(s):  
Ying S. Hu ◽  
Hu Cang ◽  
Björn F. Lillemeier
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Cell Receptors ◽  
Micrometer Scale

T cells become activated when T-cell receptors (TCRs) recognize agonist peptides bound to major histocompatibility complex molecules on antigen-presenting cells. T-cell activation critically relies on the spatiotemporal arrangements of TCRs on the plasma membrane. However, the molecular organizations of TCRs on lymph node-resident T cells have not yet been determined, owing to the diffraction limit of light. Here we visualized nanometer- and micrometer-scale TCR distributions in lymph nodes by light sheet direct stochastic optical reconstruction microscopy (dSTORM) and structured illumination microscopy (SIM). This dSTORM and SIM approach provides the first evidence, to our knowledge, of multiscale reorganization of TCRs during in vivo immune responses. We observed nanometer-scale plasma membrane domains, known as protein islands, on naïve T cells. These protein islands were enriched within micrometer-sized surface areas that we call territories. In vivo T-cell activation caused the TCR territories to contract, leading to the coalescence of protein islands and formation of stable TCR microclusters.

scholarly journals Mutation in Fas Ligand Impairs Maturation of Thymocytes Bearing Moderate Affinity T Cell Receptors

2003 ◽  
Vol 198 (2) ◽  
pp. 349-360 ◽  
Author(s):  
Tamar E. Boursalian ◽  
Pamela J. Fink
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Fas Ligand ◽  
Costimulatory Molecule ◽  
Thymocyte Development ◽  
Cell Receptors ◽  
Accessory Molecule

Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells. We now extend the role of Fas ligand by showing that it can also influence thymocyte development. T cell maturation in some, but not all, strains of TCR transgenic mice is severely impaired in thymocytes expressing mutant Fas ligand incapable of interacting with Fas. Mutant Fas ligand inhibits neither negative selection nor death by neglect. Instead, it appears to modulate positive selection of thymocytes expressing both class I– and class II–restricted T cell receptors of moderate affinity for their positively selecting ligands. Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

scholarly journals Correlation Between the Number of T Cell Receptors Required for T Cell Activation and TCR–Ligand Affinity

Immunity ◽  
1996 ◽  
Vol 5 (2) ◽  
pp. 137-146 ◽  
Author(s):  
Beth A. Schodin ◽  
Theodore J. Tsomides ◽  
David M. Kranz
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Cell Receptors ◽  
Ligand Affinity

scholarly journals Interaction of CD31 with a heterophilic counterreceptor involved in downregulation of human T cell responses.

1996 ◽  
Vol 184 (1) ◽  
pp. 41-50 ◽  
Author(s):  
E Prager ◽  
R Sunder-Plassmann ◽  
C Hansmann ◽  
C Koch ◽  
W Holter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Types ◽  
Interleukin 4 ◽  
Single Chain ◽  
Necrosis Factor Alpha ◽  
Human T Cell

CD31 is a 130-kD glycoprotein of the immunoglobulin (Ig) superfamily expressed on the surface of endothelial cells, platelets, and several leukocyte subsets. Previous reports indicated that CD31 can mediate intercellular adhesion via both homophilic and heterophilic interaction mechanisms. Using a soluble recombinant CD31-Ig fusion protein (CD31 receptor globulin [Rg]), we demonstrate here that human CD31- T lymphocytes and CD4+CD31- T cell clones express a heterophilic CD31 ligand that is upregulated 18 h after activation. Interaction of CD31Rg with CD31- T helper cell (Th) clones was divalent cation independent but could be blocked by heparin, thus indicating that the CD31 counterreceptor on T cells can be distinguished from the ligands identified on other cell types. Moreover, a single chain protein of 120 kD was precipitated by CD31Rg from the lysates of CD31- Th clones. CD31Rg completely downregulated the proliferative response and cytokine production (interleukin-4, interferon-gamma, and tumor necrosis factor-alpha) of CD31- Th clones when the cells were maximally stimulated via immobilized CD3 monoclonal antibody. These results suggest that interaction of CD31 with a heterophilic counterreceptor on T lymphocytes can interfere with a positive regulatory pathway of T cell activation, or directly signal T cells to downregulate immune function.

scholarly journals Kinetics of transcription factors regulating the RANTES chemokine gene reveal a developmental switch in nuclear events during T-lymphocyte maturation.

1996 ◽  
Vol 16 (1) ◽  
pp. 202-210 ◽  
Author(s):  
B D Ortiz ◽  
A M Krensky ◽  
P J Nelson
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Types ◽  
Cis Acting ◽  
Early Expression ◽  
Nuclear Events ◽  
Rantes Promoter ◽  
Developmental Switch

RANTES is a chemoattractant cytokine (chemokine) whose gene is expressed immediately after stimulation of several cell types but upregulated late (3 to 5 days) after activation in normal T lymphocytes. Here we describe two cis-acting elements in the human RANTES promoter that act in T lymphocytes. One site interacts with NFIL6, which is activated within the first 24 h after T-cell activation. The second site binds an apparently novel complex that is upregulated later, between days 3 and 5. These data provide an explanation for the immediate-early expression of RANTES in some cell types and identify apparently novel factors contributing to late RANTES transcription in T cells. The results reveal a developmental switch occurring during normal T-cell maturation coincident with the onset of terminal differentiation and the binding of late-acting factors to sequences of the RANTES promoter.

High affinity T cell receptors from yeast display libraries block T cell activation by superantigens11Edited by I. A. Wilson

2001 ◽  
Vol 307 (5) ◽  
pp. 1305-1315 ◽  
Author(s):  
Michele C Kieke ◽  
Eric Sundberg ◽  
Eric V Shusta ◽  
Roy A Mariuzza ◽  
K.Dane Wittrup ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Yeast Display ◽  
Cell Receptors ◽  
High Affinity

scholarly journals Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2021 ◽  
Vol 6 (57) ◽  
pp. eabf7570
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Adult Disease ◽  
Vasoactive Medication ◽  
Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

scholarly journals Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽  
2021 ◽  
Author(s):  
Justina X. Caushi ◽  
Jiajia Zhang ◽  
Zhicheng Ji ◽  
Ajay Vaghasia ◽  
Boyang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
T Cell Receptors ◽  
Tumour Microenvironment ◽  
Lung Cancers ◽  
Cell Receptors ◽  
Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

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