Rational design of biologically active peptides: inhibition of T cell activation through interference with CD 4 function

2000 ◽  
Vol 13 (0) ◽  
pp. S306-S310 ◽  
Author(s):  
U. Pozzetto ◽  
A. Facchiano ◽  
F. Serino
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Rational Design ◽  
Cell Activation ◽  
Biologically Active ◽  
Active Peptides ◽  
Biologically Active Peptides

How many dendritic cells are required to initiate a T-cell response?

Blood ◽  
2012 ◽  
Vol 120 (19) ◽  
pp. 3945-3948 ◽  
Author(s):  
Susanna Celli ◽  
Mark Day ◽  
Andreas J. Müller ◽  
Carmen Molina-Paris ◽  
Grant Lythe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Response ◽  
Rational Design ◽  
Cell Activation ◽  
T Cell Response ◽  
Cell Responses ◽  
Precursor Frequency

Abstract T-cell activation in lymph nodes relies on encounters with antigen (Ag)–bearing dendritic cells (DCs) but the number of DCs required to initiate an immune response is unknown. Here we have used a combination of flow cytometry, 2-photon imaging, and computational modeling to quantify the probability of T cell–DC encounters. We calculated that the chance for a T cell residing 24 hours in a murine popliteal lymph nodes to interact with a DC was 8%, 58%, and 99% in the presence of 10, 100, and 1000 Ag-bearing DCs, respectively. Our results reveal the existence of a threshold in DC numbers below which T-cell responses fail to be elicited for probabilistic reasons. In mice and probably humans, we estimate that a minimum of 85 DCs are required to initiate a T-cell response when starting from precursor frequency of 10−6. Our results have implications for the rational design of DC-based vaccines.

scholarly journals T cell Receptor Vβ9 in Method for Rapidly Quantifying Active Staphylococcal Enterotoxin Type-A without Live Animals

Toxins ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 399 ◽  
Author(s):  
Reuven Rasooly ◽  
Paula Do ◽  
Xiaohua He ◽  
Bradley Hernlem
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Current Model ◽  
Active Form ◽  
Food Poisoning ◽  
Type A ◽  
Staphylococcal Enterotoxin ◽  
Biologically Active ◽  
Accessory Cells

Staphylococcal food poisoning is a result of ingestion of Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus. Staphylococcal enterotoxin type A (SEA) is the predominant toxin produced by S. aureus strains isolated from food-poisoning outbreak cases. For public safety, assays to detect and quantify SEA ideally respond only to the active form of the toxin and this usually means employing disfavored live animal testing which suffers also from poor reproducibility and sensitivity. We developed a cell-based assay for SEA quantification in which biologically-active SEA is presented by Raji B-cells to CCRF-CEM T-cells resulting in internalization of Vβ9 within 2 hours with dose dependency over a 6-log range of SEA concentrations. This bioassay can discern biologically active SEA from heat-inactivated SEA and is specific to SEA with no cross reactivity to the homologically-similar SED or SEE. In this study, we terminated any ongoing biochemical reactions in accessory cells while retaining the morphology of the antigenic sites by using paraformaldehyde fixation and challenged the current model for mechanism of action of the SEA superantigen. We demonstrated for the first time that although fixed, dead accessory cells, having no metabolic functions to process the SEA superantigen into short peptide fragments for display on their cell surface, can instead present intact SEA to induce T-cell activation which leads to cytokine production. However, the level of cytokine secretion induced by intact SEA was statistically significantly lower than with viable accessory cells, which have the ability to internalize and process the SEA superantigen.

scholarly journals Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling

2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jennifer A. Rohrs ◽  
Pin Wang ◽  
Stacey D. Finley
Keyword(s):  
T Cell ◽  
Computational Modeling ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Rational Design ◽  
Cell Activation ◽  
Computational Models ◽  
Mechanistic Models ◽  
Design And Optimization ◽  
Endogenous Proteins

T cells in the immune system are activated by binding to foreign peptides (from an external pathogen) or mutant peptide (derived from endogenous proteins) displayed on the surface of a diseased cell. This triggers a series of intracellular signaling pathways, which ultimately dictate the response of the T cell. The insights from computational models have greatly improved our understanding of the mechanisms that control T-cell activation. In this review, we focus on the use of ordinary differential equation–based mechanistic models to study T-cell activation. We highlight several examples that demonstrate the models’ utility in answering specific questions related to T-cell activation signaling, from antigen discrimination to the feedback mechanisms that initiate transcription factor activation. In addition, we describe other modeling approaches that can be combined with mechanistic models to bridge time scales and better understand how intracellular signaling events, which occur on the order of seconds to minutes, influence phenotypic responses of T-cell activation, which occur on the order of hours to days. Overall, through concrete examples, we emphasize how computational modeling can be used to enable the rational design and optimization of immunotherapies.

scholarly journals Rational Tuning of CAR Tonic Signaling Yields Superior T-Cell Therapy for Cancer

2020 ◽  
Author(s):  
Ximin Chen ◽  
Mobina Khericha ◽  
Aliya Lakhani ◽  
Xiangzhi Meng ◽  
Emma Salvestrini ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Rational Design ◽  
Cell Activation ◽  
Cell Function ◽  
Empirical Observation ◽  
T Cell Therapy ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T

SUMMARYChimeric antigen receptors (CARs) are modular proteins capable of redirecting immune cells toward a wide variety of disease-associated antigens. Here, we explore the effects of CAR protein sequence and structure on CAR-T cell function. Based on the empirical observation that CD20 CARs with similar sequences exhibit divergent tonic-signaling and anti-tumor activities, we devised engineering strategies that aimed to improve CAR-T cell function by tuning the intensity of tonic signaling. We found that CARs designed to exhibit low but non-zero levels of tonic signaling show robust effector function upon antigen stimulation while avoiding premature functional exhaustion by CAR-T cells. Through alterations of the CAR’s ligand-binding domain and overall protein conformation, we generated CD20 CAR variants that outperform the CD19 CAR in mouse models of human lymphoma. We further demonstrate that rational modification of protein confirmation can be generalized to improve GD2 CAR-T cell efficacy against neuroblastoma. These findings point to tonic signaling and basal T-cell activation as informative parameters to guide the rational design of next-generation CARs for cancer therapy.

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