Navigating the Liver: Spatiotemporal Regulation of CD4+ T Cell Migration and Function in Hepatocyte-Targeted Immunity

• Applicant: Dr. Silja Steinmann
• Subject Area: Gastroenterology ; Immunology ; Clinical Infectiology and Tropical Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574208635

The complex interplay necessary to induce effective immune responses are usually coordinated in the lymph nodes. The liver, however, faces a unique challenge: it is constantly exposed to a wide variety of substances, many of which are beneficial or essential for metabolism, while others may be harmful. As a result, the liver must keep a fine balance by allowing protective immune responses against harmful substances, while avoiding unnecessary inflammation that could damage the organ. Recent research suggests that the liver itself can act as a site for immune cell activation and coordination, and serve as a training ground for immune responses. However, effector immune cells (CD8⁺ T cells), which are responsible for organ defence and the elimination of infected cells, often fail to fully mature when activated in the liver. This makes it difficult for the immune system to effectively clear infections that are localised in the liver, such as the hepatitis B virus. Interestingly, helper cells (CD4⁺ T cells) have recently been shown to help overcome the insufficient training of CD8⁺ T cells in the liver. CD4⁺ T cells can modulate and enhance the function of CD8⁺ T cells, enabling stronger and more effective immune responses in the organ. For this to happen, the positioning and movement of both cell types must be precisely coordinated within the liver. While some progress has been made in understanding how CD8⁺ T cells enter the liver, our understanding how CD4+ cells access this organ and interact with other immune cells remains extremely limited. In this project, I propose that CD4⁺ T cells rely on specific mechanisms to migrate into the liver and move within the tissue to carry out their regulatory roles. To investigate this, I will use a mouse model that allows CD4⁺ T cells to be tracked in detail, combined with cutting-edge techniques, including RNA sequencing, advanced imaging, and single-cell analysis, to identify the key mechanisms that govern CD4⁺ T cell entry and function in the liver. Liver samples from patients with chronic liver conditions will be analysed to investigate if the same mechanisms observed in mice are also present in humans. The results of this project will be crucial for gaining a better understanding of how CD4⁺ T cells migrate into the liver, interact with other immune cells, and contribute to immune regulation within the organ. This knowledge is essential for developing new strategies to modulate immune responses in the liver, either to enhance them during infections, or to selectively suppress them in autoimmune liver diseases.

• DFG Programme: WBP Fellowship
• International Connection: Italy
• Host: Professor Dr. Matteo Iannacone, Ph.D.