Tissue-specific, immune-mediated diseases such as inflammatory bowel disease, autoimmune hepatitis, or multiple sclerosis and metabolic diseases like non-alcoholic steatohepatitis become increasingly prevalent worldwide and the life quality of people suffering from those diseases is strongly impaired. These diseases which are predominantly autoimmune diseases, are characterized by infiltration and accumulation of immune cell populations, in particular T cells. Especially auto-antigen specific T cells are considered to be the main driver of tissue damage, particularly in autoimmune diseases. However, we lack a more detailed understanding of the identity of such auto-reactive T cells and their tissue-specific target antigens causing autoimmunity in the tissue.
We have recently identified T cell auto-aggression in non-alcoholic steatohepatitis, a disease caused by sterile inflammation, as the cause of liver tissue damage, and thereby discovered a novel principle of T cell activation leading to auto-aggression and tissue destruction independent of MHC-restricted target cell recognition (Dudek et al., Nature 2021, Pfister et al., Nature 2021). Mechanistically, we defined IL-15 signaling as a major pathway for the generation of auto-aggressive CXCR6+ CD8 T cells in mice and men. Independent of MHC-restricted target cell recognition, these cells recognize danger signals like extracellular ATP and NAD through the purinergic receptor P2XR7 that induces Fas-FasL-dependent killing of target cells. This novel concept of T cell effector function that shares features with innate-like lymphocytes opens a whole new field in T cell biology and sheds new light in the understanding of T-cell mediated tissue damage during immune responses in the absence of antigen-dependent activation. Based on this novel concept of T cell-mediated destruction of tissues in diseases, our research group addresses the following topics to identify novel targets to treat patients with autoimmune diseases:
1) Environmental crosstalk of T cells, mainly CD8 T cells, with other immune cells in the tissue for the generation of auto-aggressive T cells in mice and human. Defining commonalities and differences of lymphocytes that harbors TCRs specific for a broad spectrum of antigens and receptors against various environmental signals like growth factors or immune-modulatory metabolites.
2) Determination of the metabolic, transcriptional and functional profile of murine and human auto-aggressive T cells
3) Identification and characterization of stress-induced signals (membrane-bound, soluble) derived from malfunctioning target cells that activate T cells independent of TCR stimulation
To achieve our scientific goals, we use preclinical mouse models and human biological material including peripheral blood mononuclear cells (PBMCs) and tissue samples from healthy donors and patients. We mainly apply multiple methods like multidimensional flow cytometry (SONY, SP6800), time-resolved, multidimensional cytotoxicity assays (Xcelligence, Agilent and AtlaZ, Nanion) metabolic flux analysis with (Seahorse®) and mass spectrometry imaging (TimsTOF) for our analysis.
Dudek, M*., Lohr, K*., Donakonda, S. et al. IL-6 induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells. Cell reports 38, 7 (2022). *equally contributed
Dudek, M., Pfister, D., Donakonda, S. et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592, 444–449 (2021)
Pfister, D., Núñez, N.G., Pinyol, R. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021)
Conlon, T.M., John-Schuster, G., Heide, D. et al. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature 588, 151–156 (2020)
Wittlich, M*., Dudek, M*., Böttcher, JP. Liver sinusoidal endothelial cell cross-priming is supported by CD4 T cell derived IL-2. J Hepatol 66, 978-986 (2017), *equally contributed
Yahoo N, Dudek M, Knolle P, Heikenwälder M. Role of immune responses for development of NAFLD-associated liver cancer and prospects for therapeutic modulation. J Hepatol 23, S0168-8278 (2023)
Dudek, M., Knolle, PA. Nichtalkoholisch induzierte Fettleber: Wie CD8-T-Zellen das Gewebe schädigen. Dtsch Arztebl 118, 37 (2021)
Tilg, H., Adolph, T.E., Dudek, M., Knolle, PA. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity. Nat Metab 3, 1596–1607 (2021)
The complete list of our publications can be found here, on PubMed.
We are supported by institutional funds.