Lorenz, Ulrike M
Associate Professor, Microbiology, Immunology, and Cancer Biology
- Diploma, Biochemistry, Freie University, Berlin
- PhD, Biochemistry, Freie University/Max-Planck-Institut, Berlin
Charlottesville, VA 22908
Maintaining and Breaking Immune Tolerance
A healthy physiological immune system is built on a continuous balance between a productive immune response to pathogens and tolerance to self. Under patho-physiological conditions, such as loss of tolerance to self, autoimmune diseases develop. On the other hand, tolerance to tumors and the lack of an effective immune response is a hurdle that needs to be overcome in cancer immunotherapy.
For T cells, immune tolerance is achieved and maintained in two ways; central and peripheral tolerance. Central tolerance is completed during thymic T cell development when potentially auto-reactive T cells undergo cell death. Peripheral tolerance occurs at many levels, one of which is mediated by a specialized subtype of T cells, the so-called regulatory T cells (Tregs), which have been shown to suppress the immune response and thereby control potentially harmful responses to self. It is now widely accepted that dysregulated Treg cell-mediated suppression is a major contributor of autoimmune diseases, and that the induction/activation of Treg cells can promote tumor tolerance both naturally and during anti-tumor immune therapy.
Our lab has a long-standing interest in the role of the protein tyrosine phosphatase SHP-1 in T cell activation, development, and function. Over the last years, our focus has shifted to the role of SHP-1 in regulating the balance between T cell activation and suppression.
We have recently generated several new mouse models to specifically interfere with SHP-1 activity in T cell subsets. Using these models, we identified a novel, previously unappreciated mechanism of SHP-1 influencing immune tolerance by affecting the susceptibility of conventional T cells to regulatory T cell-mediated suppression. We are currently working on how SHP-1 modulates downstream signaling molecules and thereby controls the susceptibility to suppression as well as how SHP-1 modulates the activity of Treg cells. These projects have implications for the prevention/treatment of autoimmune diseases as well as boosting tumor immunity.
Complementing our genetic approaches, we have recently developed a novel protein degron system that allows for fast, but reversible highly specific protein depletion in vitro and in vivo. We are currently using this approach to improve the safety of chimeric antigen receptor (CAR) T cells. While the recent CAR T cell therapies have shown impressive efficacy, the amount of associated severe morbidities is significant. Improving the safety is therefore of great clinical interest.