Research Division: Immunology
Description Text
The immune system has evolved over time to defeat external threats such as bacteria and viruses, as well as internal threats like cancer. The ability of the immune system to destroy such a diverse number of foreign invaders is a tribute to its robustness. However, this comes at a price and its complexity can result in severe complications. In some diseases, such as autoimmune diseases and chronic inflammation, the immune system actually contributes through a misdirected immune response. In other diseases, such as cancer or chronic infections, an insufficient immune response leads to disease progression. More recently, misguided or deregulated immune responses have been implicated in non-classical immune disorders such as obesity, cardiovascular diseases, and fibrosis.
Understanding complex immune responses and their switch points in the tissue context is crucial to manipulating immune reactions in a tissue-targeted manner. And it is precisely at the interface of where these switch points occur that the Division of Immunology focuses its efforts. Inflammation and tissue regeneration are connected processes within tissues. An important function, in this context, is the ability of specialized immune cells, such as regulatory T cells (Tregs), to direct local immune responses, as well as to organize tissue repair and tissue homeostasis. To induce tissue-regeneration processes, immune cells have to communicate with tissue-resident cells such as stem cells, epithelial cells, fibroblasts and other tissue-immune cells. This tissue-immune communication leading to tissue regeneration is likely highly relevant in understanding cancer progression and metastasis.
Research into immune cell functions in tissues such as regeneration and organ homeostasis is still in its infancy. To this day, we have limited understanding of important molecular mechanisms and interaction agents. But the Division of Immunology is looking to change that.
Targeted therapeutic manipulation of different aspects of tissue immunology is underway. These include: tissue-resident immune cell differentiation; tissue-immune communication; wound healing; and tissue homeostasis by immune cells. This research will enable the development of tailored immunotherapies for the treatment of chronic inflammation, autoimmune diseases and transplant rejection. Such therapies will also be applicable in the treatment of tumours.
To explore how regulatory mechanisms can be exploited in an immunotherapeutic way, the Institute is on a mission to develop new artificial immune networks. Using synthetic immunology tools, the Division of Immunology seeks to transfer the basic findings surrounding targeting and mechanisms into novel immunotherapies through the generation of engineered immune cells. The aim is to engineer immune cells to be more flexible in their recognition of targets and enhance their functionality.
Regulatory T cells
The self-regulation of the immune system is mediated by a specialized immune cell population known as regulatory T cells (Tregs). These Treg cells are able to monitor other immune cells and reduce their activity. In addition, a specialized subset of Treg cells or ’tissue-Treg cells,’ which are located in organs and tissues, can contribute to tissue regeneration, homeostasis and healing of injuries. The Division aims to better understand the tissue-type differentiation and their function (Delacher et al. Nature Immunology, 2017). The differentiation into the tissue-Treg phenotype starts in precursors in lymphoid organs and ends in the tissues (Delacher et al. Immunity, 2020). We recently characterized human tissue-Tregs on a molecular level (Delacher et al. Immunity, 2021). In our ongoing research, we are investigating how these cells contribute to homeostasis and tissue regeneration. We are also examining which factors, molecules, and mechanisms are used to communicate with tissue cells to trigger the regeneration processes.
A variety of modern technologies and different experimental systems are in place to study populations of Treg cells. These include epigenetic and single-cell sequencing technologies, genome editing methods, and different 3D organoid model systems. In vivo and in vitro model systems are also used to study therapeutic intervention in cancer, transplantation, Graft-versus-Host-Disease (GvHD) and chronic inflammation.
Communication between tissue and immune cells
Our body’s tissues consist of various different cells. One important component is the immune cells which influence other tissue cells and also play a role in tissue remodeling. They communicate in different ways with tissue-resident cells such as fibroblasts, epithelial cells, and tissue stem cells. Some, for example, produce different messenger substances which act on these tissue cells and lead to changes in cell-to-cell communication, cell differentiation and cell growth. But tissue cells can also influence the function of tissue-resident immune cells and thus control immune responses.
Consequently, both immune and tissue cells—and their interactions—work in symbiosis in times of inflammation and are critical in the maintenance of tissue homeostasis and wound healing. Of course, if that balance is disturbed, various diseases may occur. For example, a deregulation of fibroblasts can lead to uncontrolled wound healing and fibrotic diseases, as well as tumor growth and metastasis. In fact, so-called ‘tumor-associated fibroblasts’ have been found to have a contributory effect in tumor growth. This happens when they create an environment that promotes tumor-cell proliferation and metastasis formation, while inhibiting the anti-tumor activity of the immune system. Our ongoing research will investigate tissue-to-immune cell communication, and also focus on immune cell-to-fibroblast and immune cell-to-epithelial cell interactions.
Synthetic Immunology and artificial immune receptors
Synthetic Immunology is the artificial design of synthetic systems that are able to perform novel immunological functions. With this in mind, the Institute’s focus is on the design of new artificial signaling networks that either allow new immunological functions to be implemented in immune cells, or reprogram immune cells so that they can perform new functions for cellular immunotherapy.
We have two specific objectives. Firstly, we are seeking to generate synthetic genetic modules to instruct Tregs to control inflammation and support tissue regeneration. Secondly, we are seeking to strengthen effector T cells to better combat cancer. A good example of this is a project we are running focused on using artificial immune receptors as novel biosensors (Bittner et al. PNAS, 2022). Here, artificial sensors are developed to help Treg cells sense inflammation better and fight it more effectively. To this end, Treg cells are reprogrammed and equipped with new functionality with the goal of developing innovative therapeutic concepts for the treatment of inflammatory diseases.
Research Team
Prof. Markus Feuerer
Deputy Scientific Director LIT & Head of Research Division | Immunology