Dataset Information

ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3? Phosphorylation.

ABSTRACT: Chimeric antigen receptors (CARs) are engineered receptors that mediate T cell activation. CARs are comprised of activating and co-stimulatory intracellular signaling domains derived from endogenous T cells that initiate signaling required for T cell activation, including ERK activation through the MAPK pathway. Understanding the mechanisms by which co-stimulatory domains influence signaling can help guide the design of next-generation CARs. Therefore, we constructed an experimentally validated computational model of anti-CD19 CARs in T cells bearing the CD3? domain alone or in combination with CD28. We performed a systematic analysis to explore the different mechanisms of CD28 co-stimulation on the ERK response time. Comparing these model simulations with experimental data indicates that CD28 primarily influences ERK activation by enhancing the phosphorylation kinetics of CD3?. Overall, we present a mechanistic mathematical modeling framework that can be used to gain insights into the mechanism of CAR T cell activation and produce new testable hypotheses.

SUBMITTER: Rohrs JA

PROVIDER: S-EPMC7178546 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation.

Rohrs Jennifer A JA Siegler Elizabeth L EL Wang Pin P Finley Stacey D SD

iScience 20200330 4

Chimeric antigen receptors (CARs) are engineered receptors that mediate T cell activation. CARs are comprised of activating and co-stimulatory intracellular signaling domains derived from endogenous T cells that initiate signaling required for T cell activation, including ERK activation through the MAPK pathway. Understanding the mechanisms by which co-stimulatory domains influence signaling can help guide the design of next-generation CARs. Therefore, we constructed an experimentally validated ...[more]

PMID: 32325413

Similar Datasets

Project description:BackgroundChronic persistent infections have been associated with T lymphocytes functional impairment. The aim of this study was to compare the activation status, the proliferative potential and the expression of CD28 and CD3ζ chain on T lymphocytes between chronic chagasic patients and uninfected controls.Methodology/principal findingsForty-two chronic chagasic patients, 28 healthy individuals and 32 non-chagasic cardiomyopathy donors were included. Peripheral blood was marked for CD3, CD4, CD8, HLA-DR, CD28, CD38 and intracellular CD3ζ. Peripheral blood mononuclear cells were stained with carboxyfluorescein diacetate succinimidylester and incubated with T. cruzi lysate or phytohemagglutinin for five days. Cells from 3 healthy controls were incubated with T. cruzi trypomastigotes separated with transwells; and the expression of CD3ζ chain and proliferation index was determined. Heart-infiltrating cells from two chronic chagasic patients were tested for the aforementioned cellular markers. Chagasic patients displayed higher frequencies of CD4+/HLA-DR+/CD38+ (8.1% ± 6.1) and CD8+/HLA-DR+/CD38+ (19.8 ± 8.9) T cells in comparison with healthy (1.6 ± 1.0; 10.6 ± 8.0) and non-chagasic cardiomyopathy donors (2.9 ± 2.9; 5.8 ± 6.8). Furthermore, the percentage of CD4+ activated T cells was higher in chagasic patients with cardiac involvement. CD8+ T cells proliferation index in chagasic donors (1.7 ± 0.3) was lower when compared with healthy (2.3 ± 0.3) and non-chagasic cardiomyopathy individuals (3.1 ± 1.1). The frequencies of CD4+/CD28+ and CD8+/CD28+ T cells, as well as the CD3ζ(bright)/CD3ζ(dim)% ratios in CD4+ and CD8+ were lower in chagasic patients when compared with both control groups. The CD3ζ(bright)/CD3ζ(dim)% ratio and proliferative indexes for CD4+ and CD8+ T lymphocytes decreased gradually in those cells cultivated with parasites and displayed lower values than those incubated with medium alone. Finally, heart-infiltrating T cells from two T. cruzi infected patients also expressed activation markers and down-regulate CD28 and CD3ζ.ConclusionsCD8+ T lymphocytes from chagasic donors displayed reduced proliferative capacity, which might be associated with CD3ζ down-regulation and diminished CD28 expression on CD4 T cells.

Dataset Information

ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3? Phosphorylation.

Publications

ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets