Molecular Mechanisms of the Immune Response and Immuno-Biotechnology

Image
Molecular Mechanisms of the Immune Response and Immuno-Biotechnology
Group leader
prof_springer.jpg
Molecular Mechanisms of the Immune Response and Immuno-Biotechnology
Specific themes and goals

We have worked on the structure and biochemistry of MHC class I molecules for more than two decades. One main research focus is to describe class I intracellular quality control and trafficking. Class I molecules, like every protein, are generated inside the cell, where they also bind the peptide. But they fulfill their role at the cell surface, where the bound virus or tumor fragment (antigen) is presented to specialized immune cells called cytotoxic T cells (CTL). Quality control and trafficking of class I molecules are tightly regulated processes, strictly dependent on the presence of the peptide. We investigate the mechanisms that move class I molecules to the cell surface and then back inside (endocytosis) and their manipulation by viruses. Recently, we discovered novel dimeric forms of class I on the cell surface. MHC class I molecules are also tools in practical applications. When bound to a specific peptide, they can be used to stain, isolate, and activate specific CTL from patients. These activated immune cells can then, for example, be re-infused into the patient to clear an infection or stop tumor growth. We develop MHC class I-based reagents for that purpose. 

In the last 20 years, we have contributed substantially to both basic and applied MHC class I research. We are especially interested in synergies between the two, and use state-of-the-art techniques from cell biology, biochemistry, biophysics, biotechnology, and computational biology.

Highlights and impact
  • MHC clusters — We have discovered that MHC class I molecules form clusters at the cell surface, with each other and with other proteins. We have investigated these clusters at a level of detail unprecedented in the literature. We are currently engaged in describing these clusters and their cellular role. 
  • Viral immune escape — Viruses often try to block antigen presentation using proteins called immunoevasins. We have described the mechanism of action of an immunoevasin by a herpes virus, and are currently working on another one. The results will help to further elucidate the everlasting battle between viruses and the immune system. They will allow us to better understand how herpes viruses can persist in people’s bodies throughout their lives as a result of immunoevasion. 
  • Novel reagents for tumor immunotherapy — We have invented a stabilized form of an MHC class I molecule that can be rapidly loaded with peptide. This allows the rapid generation of so-called MHC tetramers, which are important reagents for the detection of tumor-specific T cells in patients. We have licensed this patented technology to several companies, and we set up our own company, Tetramer Shop, to market it.
Group composition & projects/funding

Our group has two postdocs, two PhD students, one technician, and several undergraduates. We are funded by the Deutsche Forschungsgemeinschaft and the Tönjes Vagt Foundation of Bremen.

Selected publications
  • C. Dirscherl, S. Löchte, Z. Hein, J-D. Kopicki, A. R. Harders, N. Linden, A. Karner, J. Preiner, J. Weghuber, M. Garcia-Alai, C. Uetrecht, M. Zacharias, J. Piehler, P. Lanzerstorfer, S. Springer. Dissociation of β2m from MHC class I triggers formation of noncovalent transient heavy chain dimers. J. Cell Sci. (2022). 
  • Raghavendra Anjanappa, Maria Garcia-Alai, Janine-Denise Kopicki, Julia Lockhauserbäumer, Mohamed Aboelmagd, Janina Hinrichs, Ioana Maria Nemtanu, Charlotte Uetrecht, Martin Zacharias, Sebastian Springer*, and Rob Meijers*: Structures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection. Nature Communications 11, 1314 (2020). 
  • A. Moritz, R. Anjanappa, C. Wagner, S. Bunk, M. Hofmann, G. Pszolla, A. Saikia, M. Garcia-Alai, R. Meijers, H-G. Rammensee, S. Springer, and D. Maurer. High-throughput peptide-MHC complex generation and kinetic screenings of TCRs with peptide-receptive HLAA*02:01 molecules. Science Immunology 4 (2019). 
  • S. Kumar Saini, T. Tamhane, R. Anjanappa, A. Saikia, S. Ramskov, M. Donia, I.M. Svane, S.N. Jakobsen, M. Garcia-Alai, M. Zacharias, R. Meijers, S. Springer, and S. R. Hadrup. Empty peptide-receptive MHC class I molecules for efficient detection of antigen-specific T cells. Science Immunology 4 (2019). 
  • V.R. Ramnarayan, Z. Hein, L. Janßen, N. Lis, S. Ghanwat, and S. Springer. Cytomegalovirus gp40/m152 uses TMED10 as ER anchor to retain MHC class I. Cell Reports 23 (2018).