The effector function of the immune system is a finely tuned orchestration of stimulatory and regulatory signals mediated by various factors and cells. An imbalance can lead to an inadequate immune response against pathogens, resulting in chronic infections or to hyperactivation of the immune system, leading to autoimmunity and tissue damage.
In addition to cytokines and receptor-ligand interactions, it is primarily specialized immune cells that mediate this regulation. In addition to regulatory T cells (Tregs), these are mainly myeloid-derived suppressor cells (MDSCs), which are able to attenuate or block excessive immune responses.
MDSCs are a heterogeneous population of myeloid cells that can be induced in pathological conditions as well as during therapeutic vaccination. Based on their markers, these cells are divided into polymorphonuclear (PMN)-MDSCs (CD11b+MHC-II-Ly-6G+Ly-6Clow (Gr-1high) for mice and CD11b+MHC-II-CD14-CD15+ in humans) and monocytic (M)-MDSCs (CD11b+MHC-II-Ly-6G+Ly-6Clow (Gr-1high) for mice and CD11b+MHC-II-CD14-CD15+ in humans).
The main focus of our group is on the induction, function, and interaction of monocytes and MDSCs with other immune cells and how they affect effector function. While monocytes are able to enhance the local immune response,
MDSCs can block the function of effector cells, especially T cells and NK cells. We demonstrated that suppression of T cells occurs via cytosolic transfer of the radical methylglyoxal, which leads to intracellular depletion of L-arginine in T cells, thereby inhibiting signal transduction, particularly phosphorylation of mTOR, resulting in functional impairment of these effector cells.
We are investigating whether functional blockade of MDSCs in combination therapy with stimulating factors can positively impact the progression of tumor diseases or whether modulation of MDSCs can be used for immunotherapeutic approaches in solid tumors.
In addition to the suppression of MDSCs, we also investigate the direct interaction of tumor cells and immune cells, particularly regulating effector function in leukemias and lymphomas.
A second focus is detecting extracellular vesicles (EVs) with spectral flow cytometry. EVs are subcellular particles ranging in size from 80 - 300 nm and are secreted by all cells. Currently, the gold standard for the detection of EVs is to isolate these particles and analyze them in the aggregate, thus losing information from rare EVs. We are investigating whether it is possible to optimize spectral flow cytometry to detect individual EVs and whether these can be assigned to specific tissue types. The aim is to detect tissue-specific pathological processes at an early stage in order to make them usable for diagnostic and therapeutic purposes.
- T. Baumann, A. Dunkel, C. Schmid, S. Schmitt, M. Hiltensperger, K. Lohr, V. Laketa, S. Donakonda, U. Ahting, B. Lorenz-Depiereux, J. Heil, J, Schredelseker, L. Simeoni, C. Fecher, N. Körber, T. Bauer, N. Hüser, D. Hartmann, M. Laschinger, K. Eyerich, S. Eyerich, M. Anton, M. Streeter, T. Wang, B. Schraven, D. Spiegel, F. F. Assaad, T. Misgeld, H. Zischka, P. J. Murray, A. Heine, M. Heikenwälder, T. Korn, C. Dawid, T. Hofmann, P.A. Knolle & B. Höchst Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal. Nature Immunol.2020 Apr,23 (21):555-566. doi:10.1038/s41590-020-0666-9
- Knier B, Hiltensperger M, Sie C, Aly L, Lepennetier G, Engleitner T, Garg G, Muschaweckh A, Mitsdörffer M, Koedel U, Höchst B, Knolle P, Gunzer M, Hemmer B, Rad R, Merkler D, Korn T. Nat Immunol. 2018 Dec;19(12):1341-1351. doi: 10.1038/s41590-018-0237-5.
- Heine A, Flores C, Gevensleben H, Diehl L, Heikenwalder M, Ringelhan M, Janssen KP, Nitsche U, Garbi N, Brossart P, Knolle PA, Kurts C, Höchst. Oncoimmunology. 2017 Jun 16;6(8):e1338995. doi: 10.1080/2162402X.2017.1338995.
- Heine A, Schilling J, Grünwald B, Krüger A, Gevensleben H, Held SA, Garbi N, Kurts C, Brossart P, Knolle P, Diehl L, Höchst B. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother. doi: 10.1007/s00262-015-1790-5.
- Bastian Höchst, Julita Mikulec, Tania Baccega, Christina Metzger, Meike Welz, Julia Peusquens, Frank Tacke, Percy Knolle, Christian Kurts, Linda Diehl and Isis Ludwig-Portugall Differential induction of Ly6G and Ly6C positive myeloid derived suppressor cells in chronic kidney and liver inflammation and fibrosis. Plos One 2015 Mar 4;10(3):e0119662. doi: 10.1371/journal.pone.0119662.
- Bastian Höchst, Frank A. Schildberg, Pia Sauerborn, Yvonne A. Gäbel, Lukas C. Heukamp, Matthias Ballmaier, Friederike Gieseke, Ingo Müller, Christian Kurts, Percy A. Knolle und Linda Diehl Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. Journal of Hepatology 2013 Sep;59(3):528-35. doi: 10.1016/j.jhep.2013.04.033.
- Bastian Hoechst, Frank A. Schildberg, Christina Metzger, Jan Boettcher, Sebastian Huss, Anderas Türler, Michael Overhaus, Andreas Knoblich, Berthold Schneider, Dimitrios Pantelis, Christian Kurts, Jörg Kalff, Percy Knolle & Linda Diehl Liver sinusoidal endothelial cells contribute to T cell tolerance to circulating carcinoembryonic antigen in mice. Hepatology 2012 Nov;56(5):1924-33. doi: 10.1002/hep.25844.
- Fei Zhao, Bastian Hoechst, Austin Duffy, Jaba Gamrekalashvili, Suzanne Fioravanti, Michael P. Manns, Tim Greten, Firouzeh Korangy S100A9 a new marker for myeloid derived suppressor cells. Immunology 2012 Jun;136(2):176-83. doi: 10.1111/j.1365-2567.2012.03566.x.
- Fei Zhao, Bastian Höchst, Jaba Gamrekalasvilli, Lars Ormandy, Kris Ylaya, Xin Wang, Stephen Hewitt, Michael Manns, Firouzeh Korangy, Tim Greten Human CCR4+CCR5+Th17 cells suppress autologous CD8+ T cell responses in hepatocellular carcinoma. J Immunol. 2012 Jun 15;188(12):6055-62. doi: 10.4049/jimmunol.1102918
- Bastian Höchst, Jaba Gamrekalasvilli, Micheal Manns, Tim Greten, Firouzeh Korangy Plasticity of regulatory T cells and and Th17 cells is orchestred by different subsets of myeloid cells. Blood 2011 Jun 16;117(24):6532-41. doi: 10.1182/blood-2010-11-317321.
- Bastian Hoechst, Torsten Voigtlaender, Lars Ormandy, Jaba Gamrekalashvili, Fei Zhao, Heiner Wedemeyer, Frank Lehner, Michael P. Manns, Tim F. Greten, Firouzeh Korangy Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009 Sep;50(3):799-807. doi: 10.1002/hep.23054.
- Bastian Hoechst, Lars A. Ormandy, Matthias Ballmaier, Frank Lehner, Christine Krüger, Michael P. Manns, Tim F. Greten, Firouzeh Korangy A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+FoxP3+ T cells. Gastroenterology 2008 Jul;135(1):234-43. doi: 10.1053/j.gastro.2008
The current list of our publications can be found on Pubmed.
We would like to thank the Wilhelm sander Foundation, the Jóse Carreras Foundation and the Bavarian State Ministry for Science and the Arts for their support.