Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub

  • Nat Immunol. 2014 Apr;15(4):384-392. doi: 10.1038/ni.2843.
Romain Roncagalli  #  1  2  3 ,  Simon Hauri  #  4  5 ,  Fréderic Fiore  6  7  8 ,  Yinming Liang  1  2  3 ,  Zhi Chen  9 ,  Amandine Sansoni  6  7  8 ,  Kartiek Kanduri  9 ,  Rachel Joly  1  2  3 ,  Aurélie Malzac  1  2  3 ,  Harri Lähdesmäki  9  10 ,  Riitta Lahesmaa  9 ,  Sho Yamasaki  11 ,  Takashi Saito  12 ,  Marie Malissen  1  2  3 ,  Ruedi Aebersold  4  13 ,  Matthias Gstaiger  4  5 ,  Bernard Malissen  1  2  3  6  7  8
Affiliations
  • 1. Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université, Marseille, France.
  • 2. INSERM U1104, Marseille, France.
  • 3. CNRS UMR7280, Marseille, France.
  • 4. Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
  • 5. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, Switzerland.
  • 6. Centre d'Immunophénomique, UM2 Aix-Marseille Université, Marseille, France.
  • 7. INSERM US012, Marseille, France.
  • 8. CNRS UMS3367, Marseille, France.
  • 9. Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
  • 10. Department of Information and Computer Science, Aalto University, Finland.
  • 11. Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 12. RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
  • 13. Faculty of Science, University of Zurich, Zurich, Switzerland.
  • # Contributed equally.
PMID: 24584089 DOI: 10.1038/ni.2843
Abstract

T cell antigen receptor (TCR)-mediated activation of T cells requires the interaction of dozens of proteins. Here we used quantitative mass spectrometry and activated primary CD4(+) T cells from mice in which a tag for affinity purification was knocked into several genes to determine the composition and dynamics of multiprotein complexes that formed around the kinase Zap70 and the adaptors Lat and SLP-76. Most of the 112 high-confidence time-resolved protein interactions we observed were previously unknown. The surface receptor CD6 was able to initiate its own signaling pathway by recruiting SLP-76 and the guanine nucleotide-exchange factor Vav1 regardless of the presence of Lat. Our findings provide a more complete model of TCR signaling in which CD6 constitutes a signaling hub that contributes to the diversification of TCR signaling.