Prof. Dr. Wolfgang Schamel
Prof. Dr. Wolfgang Schamel
Institute of Biology III (Molecular Immunology) and BIOSS Centre for Biological Signalling Studies, University of Freiburg
Centre of Chronic Immunodeficiency, University Medical Centre Freiburg
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:
- Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol.
Wang F, Beck-García K, Zorzin C, Schamel WW, Davis MM (2016).
Nat Immunol 17(7):844-50.
- 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, Molnár E, Schulze AK, Blanco R, Borroto A, Martín-Blanco N, Alarcon B, Höfer T, Minguet S, Schamel WW (2016).
- Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells.
Deswal S, Meyer A, Fiala GJ, Eisenhardt AE, Schmitt LC, Salek M, Brummer T, Acuto O and Schamel WWA. (2013).
J Immunol 190, 1927-1935.
- Organization of the resting TCR in nanoscale oligomers.
Schamel WWA and Alarcon B. (2013).
Immunol Rev 251, 13-20.
- Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering.
Molnár E, Swamy M, Holzer M, Beck-García K, Worch R, Thiele C, Guigas G, Boye K, Luescher IF, Schwille P, Schubert R, Schamel WWA. (2012).
J Biol Chem 287, 42664-42674.
- Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes.
Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT, Valpuesta JM, Schamel WW, Alarcon B, van Santen HM (2011).
- A new vampire saga: the molecular mechanism of T cell trogocytosis.
Dopfer EP, Minguet S, Schamel WW (2011).
- Different composition of the human and the mouse gdTCR-CD3 explains different phenotypes of CD3g- and CD3d-immunodeficiencies.
Siegers GM, Swamy M, Fernández-Malave E, Minguet S, Rathmann S, Guardo AC, Pererz-Flores V, Regueiro JR, Alarcon B, Fisch P, Schamel WWA (2007).
J Exp Med 204, 2537-2544.
- Re-orientation of two TCRa/b transmits a reversible conformational change to CD3, which is necessary for T cell activation.
Minguet S, Swamy M, Alarcon B, Luescher IF, Schamel WWA (2007).
Immunity 26, 43-54.
- Recruitment of Nck by CD3e reveals a ligand-induced conformational change essential for T cell receptor signaling and immune synapse formation.
Gil D, Schamel WWA, Montoya M, Sánchez-Madrid F, Alarcón B (2002).
Cell 109, 901-912.