Prof. Dr. Wolfgang Schamel (BIOSS Speaker)

 T cells are an important part of the immune system. The T cell antigen receptor (TCR) complex binds to self-antigens with low and to foreign antigens with high affinity. It is one of the most complex receptors know to date, composed of the TCRαß, CD3εγ, CD3εδ and CD3ζζ dimers. High affinity binding leads to full phosphorylation of the CD3 subunits, resulting in the activation of signalling cascades and the activation of the T cell. This is important to initiate an immune response against the foreign antigen. In case of low affinity binding, signal transduction cascades are also triggered and are important for the survival of the cell. However, this does not lead to activation, to avoid an immune response against self-antigens.

The Schamel group uses biochemical and synthetic biology tools, in order to understand how the TCR transmits information across the plasma membrane. We could show that bivalent antigen-binding to the ectodomains of TCRαß induces a structural rearrangement at the cytoplasmic tails of CD3. This change is required for TCR activation and might expose these tails for interaction with cytoplasmic signalling proteins. Furthermore, we demonstrated that at least part of the TCRs are pre-clustered on the cell surface, and that this is involved in regulating the sensitivity of the T cell response. Currently, we are rebuilding the pre-clustered TCRs in liposomes, in order to study the mechanisms of how these clusters form.

Recently, we have started to employ systems biology approaches, to get a quantitative and dynamic understanding of the intracellular signalling network that is downstream of the TCR. Starting with the very upstream events, we discovered a novel mechanism with which T cells can discriminate between low and high affinity antigens.

10 selected publications

• Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response.
  Baeuerle PA, Ding J, Patel E, Thorausch N, Horton H, Gierut J, Scarfo I, Choudhary R, Kiner O, Krishnamurthy J, Le B, Morath A, Baldeviano GC, Quinn J, Tavares P, Wei Q, Weiler S, Maus MV, Getts D, Schamel WW, Hofmeister R (2019).
  Nat Commun. 10(1):2087
• Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor.
  Yousefi OS, Günther M, Hörner M, Chalupsky J, Wess M, Brandl SM, Smith RW, Fleck C, Kunkel T, Zurbriggen MD, Höfer T, Weber W, Schamel WW (2019).
  Elife. 8. pii: e42475
• Light-Controlled Affinity Purification of Protein Complexes Exemplified by the Resting ZAP70 Interactome.
  Hörner M, Eble J, Yousefi OS, Schwarz J, Warscheid B, Weber W, Schamel WWA (2019).
  Front Immunol. 10:226.
• A cholesterol-based allostery model of T cell receptor phosphorylation.
  Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, Dopfer EP, Molnar E, Schulze AK, Blanco R, Borroto A, Martin-Blanco N, Alarcon B, Hofer T, Minguet S, Schamel WW (2016).
  Immunity 44, 1091-101.
• Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol.
  Wang F, Beck-Garcia K, Zorzin C, Schamel WW, Davis MM (2016).
  Nat Immunol. 17, 844-50.
• Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation.
  Fiala GJ, Janowska I, Prutek F, Hobeika E, Satapathy A, Sprenger A, Plum T, Seidl M, Dengjel J, Reth M, Cesca F, Brummer T, Minguet S, Schamel WW (2015).
  J Exp Med. 212, 1693-708.
• The CD3 conformational change in the gammadelta T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing.
  Dopfer EP, Hartl FA, Oberg HH, Siegers GM, Yousefi OS, Kock S, Fiala GJ, Garcillan B, Sandstrom A, Alarcon B, Regueiro JR, Kabelitz D, Adams EJ, Minguet S, Wesch D, Fisch P, Schamel WW (2014).
  Cell Rep. 7, 1704-15.
• Full activation of the T cell receptor requires both clustering and conformational changes at CD3.
  Minguet S, Swamy M, Alarcon B, Luescher IF, Schamel WW (2007).
  Immunity 26, 43-54.
• Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response.
  Schamel WW, Arechaga I, Risueño RM, van Santen HM, Cabezas P, Risco C, Valpuesta JM, Alarcón B (2005).
  J Exp Med. 202, 493-503.
• Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation.
  Gil D, Schamel WW, Montoya M, Sánchez-Madrid F, Alarcón B (2002).
  Cell 109, 901-12.