Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation

Immunity. 2017 Mar 21;46(3):488-503. doi: 10.1016/j.immuni.2017.02.010. Epub 2017 Mar 9.


The molecular circuits by which antigens activate quiescent T cells remain poorly understood. We combined temporal profiling of the whole proteome and phosphoproteome via multiplexed isobaric labeling proteomics technology, computational pipelines for integrating multi-omics datasets, and functional perturbation to systemically reconstruct regulatory networks underlying T cell activation. T cell receptors activated the T cell proteome and phosphoproteome with discrete kinetics, marked by early dynamics of phosphorylation and delayed ribosome biogenesis and mitochondrial activation. Systems biology analyses identified multiple functional modules, active kinases, transcription factors and connectivity between them, and mitochondrial pathways including mitoribosomes and complex IV. Genetic perturbation revealed physiological roles for mitochondrial enzyme COX10-mediated oxidative phosphorylation in T cell quiescence exit. Our multi-layer proteomics profiling, integrative network analysis, and functional studies define landscapes of the T cell proteome and phosphoproteome and reveal signaling and bioenergetics pathways that mediate lymphocyte exit from quiescence.

Keywords: T cell; glycolysis; kinase; mTORC1; mitochondria; phosphoproteomics; proteomics; quiescence exit; systems biology; systems immunology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / immunology
  • Animals
  • Energy Metabolism
  • Lymphocyte Activation / immunology*
  • Mass Spectrometry
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Proteomics
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*


  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Alkyl and Aryl Transferases
  • COX10 protein, mouse