Exploring tissue-specific CD8⁺ T cell biology during adaptive immune responses

The adaptive immune system protects us from harmful microbial infections and cancer, while providing life-long immunity after vaccination. To accomplish this extraordinary feat, cellular components of the immune system, T and B cells, continuously interact with antigen-presenting cells (APCs) in lymphoid organs. A well-studied example are naïve CD8⁺ T cells interactions with dendritic cells (DCs), the most powerful APCs for this subset. This leads to CD8⁺ T cell activation, differentiation to cytotoxic effector cells and invasion of infected organs. This process contributes decisively to elimination of intracellular pathogens such as viruses, as well as tumor cells. After clearing of a pathogen, memory CD8⁺ T cells patrol the body to protect from reinfection. While the general principle of such adaptive immune responses is well established, little is known on how this dynamic process unfolds on a single cell level in the context of tissue-derived environmental cues.

Our laboratory is combining multiple platforms including multicolor flow cytometry, functional in vitro assays and high-end microscopy to “shed light” on the molecular and cellular processes that govern adaptive immune responses mediated by cytotoxic CD8⁺ T cells. We follow three lines of investigation:

• We are examining the role of key regulators of T cell activation by using genetically modified CD8⁺ T cells. Our technical platforms include flow cytometry, RNA sequencing, viral infection models, immunofluorescent analysis and twophoton microscopy (2PM) of lymphoid tissue. Using software-based analysis of key parameters, we determine the critical decision-making steps at the onset of immune responses.
• We follow CD8⁺ T cells at their effector sites, for example in exocrine glands, skin and other non-lymphoid organs and observe how these cells contribute to host protection. A special focus is on tissue-resident memory T cells that provide a first line of defense against reinfection.
• We are applying large-scale imaging techniques, Optical Projection Tomography (OPT) and Selective Plane Illumination Microscopy (SPIM) for a quantitative analysis of adaptive immune responses by visualizing the entire 3D structure of lymph nodes and other organs during inflammation.

The combination of these approaches permits to obtain unprecedented insight into the dynamic nature of the adaptive immune system on a single cell level.