期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16466-16471
DOI：10.1073/pnas.1419337111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceActivation of T lymphocytes by the rearranged T-cell receptor (TCR) conditions essentially all aspects of their differentiation and function, and variations in the efficacy of signal transduction condition pathogen resistance and autoimmune deviation. We explored the defects in signal transduction downstream of the TCR in diabetes-susceptible nonobese diabetic (NOD) mice using mass cytometry and computational processing of single-cell data. We found that small initial differences in the efficacy of triggering at the apex of the cascade result in much more profound differences downstream, with the system being set to amplify the discriminating power of initial sensing to arrive at more marked response/no response decisions within T cells. 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 pCD3{zeta} activation resonates farther down the signaling cascade and results in larger defects in activation of the ERK1/2-S6 and I{kappa}B 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 pCD3{zeta} 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.
