Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice
Year: 2014
Type: article
Abstract: Signaling from the T-cell receptor (TCR) conditions T-cell differentiation and activation, requiring exquisite sensitivity and discrimination. Using mass cytometry, a high-dimensional technique that can probe multiple signaling nodes at the single-cell level, we interrogate TCR signaling dynamics in control C57BL/6 and autoimmunity-prone nonobese diabetic (NOD) mice, which show ineffective ERK activation after TCR triggering. By quantitating signals at multiple steps along the signaling cascade and parsing the phosphorylation level of each node as a function of its predecessors, we show that a small impairment in initial pCD3ζ activation resonates farther down the signaling cascade and results in larger defects in activation of the ERK1/2-S6 and IκBα modules. This nonlinear property of TCR signaling networks, which magnifies small initial differences during signal propagation, also applies in cells from B6 mice activated at different levels of intensity. Impairment in pCD3ζ and pSLP76 is not a feedback consequence of a primary deficiency in ERK activation because no proximal signaling defect was observed in Erk2 KO T cells. These defects, which were manifest at all stages of T-cell differentiation from early thymic pre-T cells to memory T cells, may condition the imbalanced immunoregulation and tolerance in NOD T cells. More generally, this amplification of small initial differences in signal intensity may explain how T cells discriminate between closely related ligands and adopt strongly delineated cell fates.
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: National Institutes of Health, U.S. Public Health Service, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1066494976, Systems Approach to Immunity and Inflammation, G1439323877, G1638357503, G2221374616, Naive T cell homeostasis: Treg selection and survival, Modeling the Role of Differentiation in Cancer Progression, G291137109, G3006428428, G3488383117, G3824412893, G4806874352, G4897830630, G4919389345, G503642779, G5594912826, G6446138143, Naive T cell homeostasis: Treg selection and survival, Specialized Cancer Center Support Grant, Genetic variation and regulatory networks: Mechanisms and complexity, G8026139164, G842233053, Understanding Influenza and SARS-CoV-2 vaccine responses, in vivo and in vitro
OpenAlex ID: W2135956717