We are focusing on the molecular and cellular mechanisms that determine the function of CD8 T cells within liver tissue. Such regulation of T cell function in the liver occurs in the context of the unique liver microenvironment, where T cells reaching the liver with the bloodstream interact with liver sinusoidal cell populations. In the past, we have identified that liver tissue cells, such as liver sinusoidal endothelial cells, are endowed with functional properties of immune cells that include scavenging of antigens from the circulation and antigen (cross)presentation of endocytosed antigens to CD8 T cells, which leads to the generation of dysfunctional T cells. We have further identified that the accumulation of inflammatory monocytes in the liver during acute local inflammation educates T cells for clearance of persistent Hepatitis B Virus (HBV) infection. In contrast, continuous TNF or type I Interferon signaling during chronic inflammation is associated with the loss of CD4 T cell support of CD8 T cell immunity or increased expression of IL-10 by myeloid cells to limit CD8 T cell function respectively. 

More recently, we have turned our attention to characterizing the impact of metabolites on regulating immune cell functions in tissues. We discovered that transcriptional programming by IL-15 during chronic inflammation in tissues allows CD8 T cells to acquire the capacity to sense danger signals from the environment, such as extracellular ATP. This metabolite-induced activation of CD8 T cells without T cell receptor signaling leads to antigen-independent killing of neighboring cells, which we termed auto-aggressive killing. Auto-aggressive CD8 T cells mediate immune pathology in diseases characterized by sterile inflammation like non-alcoholic steatohepatitis and drive the development of cancer cells in diseased liver tissue. 

During the SARS-CoV-2 pandemic, we took advantage of the unique possibility of studying human virus-specific immunity. We reported the importance of hybrid immunity resulting from vaccination and infection against SARS-CoV-2 proteins for protection from the development of COVID-19 by studying virus-specific T cell responses and the quality of virus-specific antibodies in infected individuals. 

Currently, we are pursuing several lines of investigation to characterize tissue-specific regulation of immune responses and how we can exploit mechanistic insights into such immune regulation for translation into the clinics. 

Local regulation of T cell immunity in the liver

During viral liver infection, virus-specific T cells can recognize their cognate antigen on MHC class I molecules on infected hepatocytes or cells cross-presenting endocytosed viral antigens released from infected hepatocytes. Due to the unique microanatomy of the liver, where T cells have to reach through endothelial fenestrae to gain access to infected hepatocytes, LSECs engage in close interaction with effector CD8 T cells. We are studying the molecular mechanisms of how LSECs regulate the function of these T cells that engage in close physical contact. Since the loss of function in virus-specific CD8 T cells, for instance, in chronic viral hepatitis, is responsible for the failure of anti-viral immunity to control infection of hepatocytes, we focus our attention on understanding the mechanistic underpinnings of this local regulation of effector T cell function by LSECs.  We further evaluate the contribution of other cell populations within the liver microenvironment to this local regulation of effector CD8 T cell function.

Moreover, we further exploit the role of auto-aggressive CD8 T cells in controlling viral infection in the liver. Since auto-aggressive CD8 T cell killing does not require cognate TCR-MHC interaction, we characterize the crosstalk between conventional and auto-aggressive CD8 T cells in eliminating virus-infected hepatocytes. Together, these projects aim at achieving immune control of liver infection even when immune cell dysfunction as a hallmark of chronic infection has already developed. 

Overcoming HBV-specific immune tolerance during chronic viral hepatitis by therapeutic vaccination

During chronic hepatitis B, HBV-specific CD8 T cells detected in patients are dysfunctional and scarce. So far, attempts have failed to reconstitute HBV-specific immunity and to control HBV infection in hepatocytes to terminate chronic infection and tissue damage leading to liver cirrhosis and liver cancer. A recently developed heterologous prime-boost therapeutic vaccination approach (TherVacB), developed by the research group of Prof. Ulrike Protzer at the Institute of Virology TUM has demonstrated superior efficacy in overcoming HBV-specific immune tolerance. In the context of an international EU-funded consortium, we are characterizing the HBV-specific immune responses after TherVacB therapeutic vaccination in phase Ib/IIa clinical studies. 

Deciphering the crosstalk of liver tissue cells and immune cells using imaging mass spectrometry and spatial single-cell RNAseq

Cell-cell communication has traditionally been studied at the level of proteins in receptor-ligand interaction. Recently, we have identified cell-cell communication to depend on the exchange of metabolites that cause functional alterations in immune cells. Since the characterization of metabolites and lipids as mediators of cell-cell communication is impossible by protein-based technologies, we explore mass spectrometry to identify cell-cell communication within tissues. Using imaging mass spectrometry in close collaboration with the laboratory of Prof. Ron Heeren from the University of Maastricht, we study cell-cell interaction and communication in liver tissue. Combining targeted and untargeted approaches, we build cell type-specific metabolome and lipidome signatures characteristic for specific functional states of immune cell populations in tissues. Machine-learning-based analysis of the cell-cell communication between liver tissue cells and immune cells detected in situ will provide us with a new level of understanding of how immune responses are fine-tuned to the tissue microenvironment.

Understanding the immune pathology of infection with pandemic pathogens

The SARS-CoV-2 pandemic has demonstrated the urgent need to understand the mechanisms determining immunopathology to organs observed during severe COVID-19 but also in the long-term consequences of SARS-CoV-2 infections. Within an interdisciplinary consortium of scientists, we will characterize the molecular mechanisms associated with the development of immunopathology upon infection with pandemic pathogens, such as SARS-CoV-2 and influenza viruses. We will determine key immunopathology-associated pathways by combining expertise from molecular virology, multi-omics profiling of immune cell populations at transcriptome, proteome, and metabolome levels, and innovative bioinformatic AI-based analysis. In further work, we will employ the knowledge of these pathways to establish molecular markers predicting the development of immunopathology and to develop targeted immune therapies to curb infection-associated immunopathology.

Strengthening anti-bacterial immunity to prevent infection

Within the Center for Infection Prevention (link to ZIP when established), a Core Institute of the Technical University of Munich located at the School of Life Science on the research campus Weihenstephan, we develop novel strategies to prevent bacterial infection. Strengthening the anti-bacterial immune defense in border organs such as the gut, lung, and skin but also the liver is at the core of this interdisciplinary research approach. Preventing infections with multi-resistant bacteria in humans and livestock is possible to approach to diminish the threat of multi-resistant bacteria, which is considered a silent but dangerous pandemic threat.